MyRisk Clinical Handbook - SciencewerkeDX

1 Myriad myRisk Clinical Handbook

For the most up-to-date clinical information please visit www.MyriadPro.com/myRisk. The format and contents of this guide are proprietary and may not be copied or used without permission from Myriad. Myriad, the Myriad logo, myRisk, the myRisk logo, MyriadPro, the MyriadPro logo, Myriad Promise, the Myriad Promise logo, myVision, the myVision logo, MySupport360, the MySupport360 logo, Pheno and MCo are either trademarks or registered trademarks of Myriad Genetics, Inc. in the United States and other jurisdictions. ©2014, Myriad Genetic Laboratories, Inc. // Updated 06/19/2014

myRisk™ Clinical Handbook

Version 2.0: 06/19/2014





About Myriad myRisk™

Myriad myRisk Hereditary Cancer Panel represents a new paradigm for clinical genetic testing for inherited cancer risk. The previous model was based on the analysis of one or a small number of genes for individual syndromes, with the choice based on consideration of the patient’s personal and family history. The new model encompasses the simultaneous analysis of a larger number of genes combined in a panel to broadly target specific cancer sites. Myriad myRisk is a 25-gene panel for the identification of clinically significant mutations impacting inherited risks for eight important cancers: breast, colorectal, ovarian, endometrial, gastric, pancreatic, melanoma and prostate.

This transition is being driven by:

1) An improved understanding of the complex genetic heterogeneity underlying many conditions, as well as the overlap in phenotypes of carriers of mutations in different genes

2) Dramatic technical advances, making it possible to analyze gene sequence and structure with much greater efficiency and lower costs than were previously possible

This myRisk clinical handbook serves as a comprehensive product manual, which will walk through and provide resources on clinical, technological and laboratory information associated with Myriad’s myRisk hereditary cancer test.

www.MyriadPro.com

Myriad Genetic Laboratories, Inc.

320 Wakara Way

Salt Lake City, UT 84108

CONTACT MYRIAD’S CUSTOMER SERVICE

Tel: (800) 469-7423

Fax: (801) 584-3615

Email: [email protected]



HEREDITARY CANCER PANEL

6 Benefits of Testing

7 Table Summary of Genes and Associated Cancers

8 Clinical and Literature Summary

9 Testing Accuracy

10 Cancer Risk Assessment

12 Patient Identification

13 Sample Submission

CANCER SITE OVERVIEW - GENERAL POPULATION

16 Breast Cancer

18 Ovarian Cancer

20 Gastric Cancer

22 Colorectal Cancer

24 Pancreatic Cancer

26 Melanoma Cancer

28 Prostate Cancer

30 Endometrial Cancer

SYNDROME & GENE OVERVIEW

33 Hereditary Breast & Ovarian Cancer (HBOC) Syndrome

• BRCA1 / BRCA2

38 Lynch Syndrome (HNPCC)

• MLH1 / MSH2 / MSH6 / PMS2 / EPCAM

49 Familial Adenomatous Polyposis (FAP) / Attenuated FAP (AFAP)

• APC

52 MUTYH-Associated Polyposis (MAP) / Associated Cancer

• MUTYH (2 copies) / MUTYH (1 copy)

54 Melanoma-Pancreatic Cancer Syndrome (M-PCS) / Melanoma Cancer Syndrome (MCS)

• CDKN2A (p16INK4A) / CDKN2A (p14ARF) / CDK4

58 Li-Fraumeni Syndrome (LFS)

• TP53

61 PTEN Hamartoma Tumor Syndrome (PHTS)

• PTEN

64 Peutz-Jeghers Syndrome (PJS)

• STK11

67 Hereditary Diffuse Gastric Cancer (HDGC)

• CDH1

69 Juvenile Polyposis Syndrome (JPS) & Hereditary Hemorrhagic Telangiectasia (HHT)

• SMAD4 / BMPR1A

72 Gene-Associated Cancer Risk

• PALB2 / CHEK2 / ATM / NBN / BARD1 / BRIP1 / RAD51C / RAD51D

SUPPLEMENTAL RESOURCES

84 Overview of Result

90 myVision: Variant Classification Program

92 Myriad myRisk™ Hereditary Cancer Technical Specifications

94 Lab Process

95 Technology FAQs

Clinical Handbook

Contents



Myriad myRisk™ Hereditary Cancer Overview



Benefits of Testing

Myriad myRisk™ evaluates the genes associated with a broad number of cancer sites

Each cancer site is associated with multiple hereditary cancer syndromes. Gene panel includes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CDK4, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11 and TP53.

Accurate Knowledge of Cancer Risks.Actionable Direction for Patient Management.

Experience

• Only Myriad has over 20 years of experience and has performed over one million hered itary cancer genetic tests

Clinically Actionable Results

• Blends genetic test status AND personal/family cancer history into clinically actionable risk assessment and follow-up

• Provides specific medical management recommendations for patients testing positive AND negative based on the guidelines of leading professional medical societies

Accurate Test Design

• Optimized primer and library design to increase test sensitivity and specificity

• All tests are powered by best-in-class variant classification techniques unique to Myriad for accurate mutation interpretation

• Validation studies to show equivalency to the gold standard set by Sanger sequencing

• Complemented by multiple customized techniques (e.g., targeted microarray) and confirmatory testing for high quality analysis of all genes

PANCREATIC

BREAST

ENDOMETRIAL

COLORECTAL

PROSTATE

MELANOMA

OVARIAN

GASTRIC

example

example

example

BRCA1BRCA2

TP53

BMPR1ASMAD4

Gene overlap:

Associated Hereditary Focus • 8 Primary Cancers

Genes Analyzed • 25 Genes

Analytical Sensitivity • >99.92%1

Average Turnaround Time • 14-21 Days

Mutation Sensitivity Compared to Single Syndrome Testing

• 40-50% increase2,3

Guideline and Family History Assessment

• National Comprehensive Cancer Network (NCCN)

• Claus Breast Cancer Risk Model • International Cancer of Pancreas

Screening (CAPS) • Amsterdam Criteria • Other

Depth of Coverage • 50x minimum, >1500x average

Intronic Coverage • Up to -20 and +10 nucleotides from

exons

Variant Classification Program • Powered by myVision™

Myriad myRisk™ Facts

1. >99.92% with lower bound 95% confidence interval. 100% concordance between NGS, Sanger Sequencing and Large Rearrangement analysis. Roa, B., et al. (2013, October). Development of a Next Generation Sequencing Panel to Assess Hereditary Cancer Risk that includes Clinical Diagnostic Analysis of the BRCA1 and BRCA2 Genes. Presented at ASHG, Boston, MA. 2. Yurgelun, MB., et al. (2014, June) Multi-gene panel testing in patients suspected to have lynch syndrome. Presented at ASCO, Chicago, IL. 3. Allen, B., et al. (2014, March) Prevalence of gene mutations among hereditary breast and ovarian cancer patients. Presented at ACMG, Nashville, TN.



Table Summary of Genes and Associated Cancers

Gene Syndrome Associated Cancers

BR OV CO EN ME PA GA PR OC

BRCA1Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

BRCA2

MLH1

Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

MSH2

MSH6

PMS2

EPCAM

APCFamilial Adenomatous Polyposis (FAP)/ Attenuated FAP (AFAP)

MUTYH MUTYH-Associated Polyposis (MAP) Cancer Risk

CDKN2A (p16INK4A) Melanoma-Pancreatic Cancer Syndrome (M-PCS)

CDKN2A (p14ARF)

Melanoma Cancer Syndrome (MCS)CDK4

TP53 Li-Fraumeni Syndrome (LFS)

PTEN PTEN Hamartoma Tumor Syndrome (PHTS)

STK11 Peutz-Jeghers Syndrome (PJS)

CDH1 Hereditary Diffuse Gastric Cancer (HDGC)

BMPR1A Juvenile Polyposis Syndrome (JPS)

SMAD4Juvenile Polyposis Syndrome (JPS) & Hereditary Hemorrhagic Telangiectasia (HHT)

PALB2 PALB2-Associated Cancer Risk

CHEK2 CHEK2-Associated Cancer Risk

ATM ATM-Associated Cancer Risk

NBN NBN-Associated Cancer Risk

BARD1 BARD1-Associated Cancer Risk

BRIP1 BRIP1-Associated Cancer Risk

RAD51C RAD51C-Associated Cancer Risk

RAD51D RAD51D-Associated Cancer Risk

BR = BreastOV = OvarianCO = Colorectal

EN = EndometrialME = MelanomaPA = Pancreatic

GA = GastricPR = ProstateOC = Other Cancers / Clinical Features

High Risk (see pg 8) Elevated Risk (see pg 8)



Myriad myRisk™ Hereditary Cancer is designed to:

Clinical and Literature Summary

A Clinical History Weighting Algorithm Accurately Classifies BRCA1 and BRCA2 Variants. Bowles et al., presented at ASHG 2013

This study presents data on two statistical reclassification tools unique to Myriad, Pheno™ and MCo™, which were developed and tested, using a dataset consisting of ~400,000 unique probands, and the algorithm was validated using a dataset consisting of ~145,000 unique probands. These tools provide reclassification certainty of greater than 99%.

4. Accurately interpret variants with Myriad’s industry-leading variant classification program

Development of a Next Generation Sequencing Panel to Assess Hereditary Cancer Risk that Includes Clinical Diagnostic Analysis of the BRCA1 and BRCA2 Genes. Roa et al., presented at ASHG 2013

This large cohort validation study compared Myriad myRisk Hereditary Cancer to Sanger sequencing for evaluation of BRCA1/2 mutations in 1,864 patient samples. The results demonstrated >99.96% analytical sensitivity and >99.99% analytical specificity (lower bound of 95% CI) for BRCA1 and BRCA2. The NGS process was refined prior to the validation of the full gene panel. In a second validation for all 25 genes, Myriad myRisk demonstrated >99.92% analytical sensitivity (lower bound of 95% CI) and 100% concordance between NGS, Sanger sequencing and large rearrangement analysis for 3,923 collective variants across all genes. Myriad myRisk was shown to be highly effective and provide accurate results equivalent to the gold standard of Sanger DNA sequencing analysis.

3. Improve quality of care by optimizing the test with gold standard analytical sensitivity

Overlap between Lynch Syndrome and Hereditary Breast and Ovarian Cancer Syndrome among Family Histories in Patients Tested for Hereditary Cancer Syndromes. Saam et al., presented at NCCN 2014

This study investigated the overlap of personal and family histories in hereditary breast and ovarian cancer (HBOC) and hereditary colon cancer. Results showed that among patients tested for HBOC, 6.9% also had family histories that meet the National Comprehensive Cancer Network (NCCN) criteria for hereditary colon cancer. Similarly, 30% of patients tested for hereditary colon cancer also met NCCN criteria for HBOC. This analysis demonstrates the clinical dilemma of test selection among at-risk patients.

2. Overcome and simplify the clinical dilemma of syndrome and gene overlap by analyzing clinically actionable genes in a broad spectrum of cancers

Prevalence of gene mutations among hereditary breast and ovarian cancer patients. Allen et al., Presented at ACMG 2014

This large prospective clinical validation study measured mutations in 25 cancer-causing genes among patients with a history of breast cancer who were referred for BRCA1/2 testing. Among the 1,781 patients evaluated, 165 (9.3%) patients tested positive for a deleterious mutation in BRCA1/2 and 79 (4.4%) for other genes with Myriad myRisk. This represents a ~48% increase in mutation detection. In a second cohort of patients previously tested negative for BRCA1/2 , the mutation rate for other genes was 3.7%.

Multi-gene Panel Testing in Patients Suspected to Have Lynch Syndrome. Yurgelun et al., presented at ASCO 2014

This study evaluated the outcomes of Myriad myRisk testing in 1,260 patients with a history of hereditary colon cancer. The results demonstrated that 9.2% of patients had deleterious mutations in Lynch syndrome genes, but an additional 3.8% were identified with deleterious mutations in other genes. This represents a ~41% increase in mutation detection.

1. Increase clinical sensitivity by identifying 40-50% more mutations in appropriate patients



Hereditary cancer panels are not all the same:The advantage of 20+ years of experience in hereditary cancer

1. >99.92% with lower bound 95% confidence interval. 100% concordance between NGS, Sanger Sequencing and Large Rearrangement analysis. Roa, B., et al. (2013, October). Development of a Next Generation Sequencing Panel to Assess Hereditary Cancer Risk that includes Clinical Diagnostic Analysis of the BRCA1 and BRCA2 Genes. Presented at ASHG, Boston, MA. 2. Bowles K., et al. (2013, October). A clinical history weighting algorithm accurately classifies BRCA1 and BRCA2 variants. Presented at ASHG, Boston, MA. 3. Eggington J., et al (2013, November) A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clin Genet. 2013 Nov 8. doi: 10.1111/cge.12315. 4. Kerr, I., et al. (2014, March). Align-GVGD, SIFT, Polyphen, MAPP-MMR, Grantham Analysis and Condel Are Weak Predictors of the Clinical Significance for Missense Variants. Presented at ACMG, Nashville, TN.

Testing Accuracy

Lab Accuracy

Accurate results lead to a greater sense of security in

patient management

Unregulated databases and inaccurate methods:

Up to 50% of classifications may be different than Myriad4

Lab X’s Claims

>99.92% gold standard analytical sensitivity1

myVision™:

>99% certainty for variant

reclassification2,3

Myriad’s Validation

99% analytical sensitivity

Finding mutations

Understanding mutations



The cancer risk estimates provided for patients with clini-

cally significant mutations in the genes included as part of

the Myriad myRisk™ panel are based on Myriad’s review and

evaluation of published literature. This is a complex process,

as published studies vary in size, quality and methodology.

There is as yet very limited information available for some

of the most recently identified genes. Therefore, the precise

numbers provided as part of the myRisk Management Tool

will change over time as we learn more about the impact of

different types of variations in these genes, and as studies

are done with larger groups of patients.

Here are some of the complexities Myriad has considered when

reviewing cancer risks for the myRisk Management Tool:

• Many studies evaluate cancer risks differently. Some indi-

cate cancer risk as a single number, a range, or as an upper

limit of the risk. Sufficient information is not always avail-

able on which to base estimates of both the upper and

lower limits of risk. As a result, cancer risks are provided

as “up to” a certain number if there is sufficient data to

support that level of risk in at least some patients with

mutations. That does not mean that every patient with a

mutation in the same gene has that level of cancer risk.

• Published studies present cancer risks in different ways,

which complicates the process of comparing information

from different studies. Data may come from studying dif-

ferent types of patients from different geographies, and

Cancer Risk Assessment

using different methods. For example, a relative cancer

risk of 3-fold to the general population in a certain coun-

try may not translate into an equivalent relative risk for

another country due to a difference in the baseline risk

assessed.

Many factors can impact cancer risks for individual patients

with gene mutations analyzed by Myriad myRisk. These

include aspects of the patient’s environment and lifestyle,

as well as mutations in other genes. As a general rule, it is

believed that a patient’s family history is one of the best

indicators of how the risk associated with a gene mutation

might be modified by other factors. Patients with family his-

tories that include multiple relatives affected with cancers

linked to their gene mutation are usually considered to have

higher cancer risks when compared with those patients with

less striking family histories, especially if those relatives were

diagnosed at younger ages.

Patients who are found to not carry a genetic mutation may

also warrant change in medical management based on per-

sonal/family history. Increased risks for cancers that have no

associated medical management recommendations are not

mentioned on the myRisk Management Tool.

Breast cancer risk based on family history is assessed using

the Claus model tables to determine when women are esti-

mated to have a greater than 20% risk for breast cancer.

Medical guidelines such as, the National Comprehensive

About High RiskFor the purposes of Myriad myRisk Hereditary Cancer, the following criteria are used to label a cancer as High Risk:

• The increase in risk must be approximately 3-fold higher than that in the general population, or higher

• The absolute risk of cancer must be approximately 5% or higher

• There must be a significant data from multiple studies supporting the cancer risk estimates

These criteria address the paradox that a 15% risk of breast cancer would not be widely considered to be especially high when compared with a 10% baseline risk in the general population, but a 15% risk for ovarian cancer would most likely be regarded as highly significant and the basis for consideration of aggressive intervention. The criteria we have used for High Risk cancers usually correlate with cancer risk levels that trigger consideration of significant changes in medical management.

About Elevated RiskFor the purposes of Myriad myRisk Hereditary Cancer, cancers are labeled as Elevated Risk if there is con-vincing data supporting any increase in risk over that of the general population, but may fall in one of the following categories:

• The estimated risk does not meet the above High Risk criteria

• Cancer risk has only been described in a single small study

• Cancer risks with which there is contradictory evidence in the current literature

There are no standard conventions for labeling a cancer risk as High versus Elevated when compared with risk in the general population.



**Guideline-based medical management recommendations may be provided if the corresponding criteria for an increased cancer risk is met; this is available at the limitation of the clinical information provided.

© 2014, Myriad Genetic Laboratories, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 800-469-7423 FX: 801-584-3615

CONFIDENTIAL

Name: Patient Name DOB: Jan 12, 1950 Accession #: 00001144-BLD Report Date: Apr 30, 2012

myRisk Management Tool Associated with:

myRisk Management Tool: Page 3 of 5

WHAT MANAGEMENT FOR CANCER RISKS SHOULD BE CONSIDERED?Clinical management guidelines are based on this patient’s personal and family history and genetic test results. Unless otherwise stated, management guidelines included below are limited to those issued by the National Comprehensive Cancer Network (NCCN). See the reference listed for more details. If management for a specifi c cancer (e.g., breast) is available due to multiple causes (e.g., a mutation and a family history, or multiple mutations in different genes), only the most aggressive management is shown. Guidelines related to the patient’s long-term care for cancer prevention are included. Guidelines for the treatment of an existing cancer are not included. Any discussion of medical management options is for general informational purposes only and does not constitute a recommendation. While genetic testing and medical society guidelines provide important and useful information, medical management decisions should be made in consultation between each patient and his or her healthcare provider.

PROCEDURE AGE TO BEGINFREQUENCY

(Unless otherwise indicated by fi ndings)

RELATED TO

FEMALE BREAST

Breast awareness- Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness1

18 years NA BRCA1

Clinical breast exam1 25 years Every 6 to 12 months BRCA1

Mammography and Breast MRI1 25 years, or individualized based on earliest diagnosis in family

Annually BRCA1

Consider options for breast cancer chemoprevention (i.e., tamoxifen)1 Individualized NA BRCA1

Consider risk-reducing mastectomy1 Individualized NA BRCA1

OVARIAN

Consider options for ovarian cancer chemoprevention (i.e., oral contraceptives)1 Individualized NA BRCA1

Bilateral salpingo-oophorectomy1

35 to 40 years, after completion of childbearing, or individualized based

on the earliest diagnosis in the familyNA BRCA1

Consider transvaginal ultrasound and CA-125 measurement1

30 years, or individualized based on earliest diagnosis in the family

Every 6 months BRCA1

PANCREATIC

Currently there are no specifi c medical management guidelines for pancreatic cancer risk

NA NA BRCA1

1. Daly M, et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 2.2013. April 25. Available at http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.

Notes for Personalized Management:myRisk Management Tool: Page 3 of 4© 2014, Myriad Genetic Laboratories, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 800-469-7423 FX: 801-584-3615

CONFIDENTIAL



WHAT MANAGEMENT FOR CANCER RISKS SHOULD BE CONSIDERED?Clinical management guidelines are based on this patient’s personal and family history and genetic test results, when appropriate. Unless otherwise stated, management guidelines included below are limited to those issued by the National Comprehensive Cancer Network (NCCN). See the reference listed for more details. If management for a specifi c cancer (e.g., breast) is available due to multiple causes (e.g., a mutation and a family history, or multiple mutations in different genes), only the most aggressive management is shown. Only guidelines for the patient’s long-term care related to cancer prevention are included. No information is provided related to treatment of a previous or existing cancer or polyps. Any discussion of medical management options is for general informational purposes only and does not constitute a recommendation. While genetic testing and medical society guidelines provide important and useful information, medical management decisions should be made in consultation between each patient and his or her healthcare provider.

Notes for Personalized Management:


(Un less o therwise ind icated by f ind ings )

RELATED TO

FEMALE BREAST

Breast Awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness1

Individualized NAPersonal /

Family History

Clinical breast exam1 30 years Every 6 to 12 monthsPersonal /

Family History

Consider breast MRI in addition to mammography1 30 years AnnuallyPersonal /

Family History

Consider risk reduction strategies1 Individualized NAPersonal /

Family History

COLORECTAL

Colonoscopy2

50 years, or individualized based on earliest polyp/cancer

diagnosis in the familyEvery 5 years

Personal / Family History

1. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 1.2012. July 16. Available at http://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf.

2. Burt RW, et al. NCCN Clinical Practice Guidelines in Oncology®: Colorectal Cancer Screening. V 1.2013. May 13. Available at http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf.


CONFIDENTIAL




OVERVIEWHereditary Breast and Ovarian Cancer Syndrome (HBOC):

• This patient has been found to have a mutation in the BRCA1 gene. Individuals with mutations in BRCA1 have a condition called Hereditary Breast and Ovarian Cancer syndrome (HBOC).

• Women with HBOC have a high risk for developing breast and ovarian cancer. There are also high risks for fallopian tube cancer and primary peritoneal cancer.

• Men with HBOC due to mutations in BRCA1 have an elevated risk for breast and prostate cancer. The increased risk for prostate cancer may be most signifi cant at younger ages.

• Male and female patients with HBOC due to mutations in BRCA1 have an elevated risk for pancreatic cancer.

• Although there are high cancer risks for patients with HBOC, there are interventions that have been shown to be effective at reducing many of these risks. Guidelines from the National Comprehensive Cancer Network (NCCN) for the medical management of patients with HBOC are listed below. It is recommended that patients with BRCA1 mutations and a diagnosis of HBOC be managed by a multidisciplinary team with experience in the prevention and treatment of the cancers associated with HBOC.

CANCER TYPE CANCER RISKRISK FOR

GENERAL POPULATIONRELATED TO

FEMALE BREAST

To age 50 Up to 51% 1.9% BRCA1


Second primary within 5 years of fi rst diagnosis 20% 2.0% BRCA1

OVARIAN



Ovarian cancer within 10 years of breast cancer diagnosis

12.7% <1% BRCA1

PANCREATIC

To age 80 Elevated Risk 1.0% BRCA1

WHAT ARE THE PATIENT’S GENE-RELATED CANCER RISKS?If more than one gene mutation increases a specifi c cancer risk (e.g., breast), only the highest cancer risk is shown. If this patient has more than one gene mutation, risk estimates may be different, as this analysis does not account for possible interactions between gene mutations.

Genetic Test Result: Page 2 of 2

CONFIDENTIAL


CONFIDENTIAL

Integrated BRACAnalysis® with Myriad myRisk™ Hereditary Cancer

myRisk Management Tool

FAMILY MEMBER

CANCER / CLINICAL DIAGNOSIS

AGE ATDIAGNOSIS

Patient None

Mother Breast 28-29†

Maternal Aunt Ovarian Not Provided

Father Colon 59

Paternal Uncle Prostate 50-59†

Maternal Cousin Lung Not Provided

This information was provided by a qualifi ed healthcare provider on the test request form and was not verifi ed by Myriad.† Age estimated based on information given. A more specifi c age may change cancer risk management suggestions provided.

RECEIVING HEALTHCARE PROVIDER

Physician Name, MDMyriad Oncology Partners320 Wakara WaySalt Lake City, UT 84108

SPECIMEN

Specimen Type: BuccalDraw Date: Apr 8, 2012Accession Date: Apr 9, 2012Report Date: Apr 30, 2012

PATIENT

Name: Patient NameDate of Birth: Jan 12, 1950Patient ID: 1144Gender: FemaleAccession #: 00001144-BLDRequisition #: 000000ORDERING PHYSICIAN: Physician Name, MD

GENETIC TEST RESULTS SUMMARY INFORMATION

PERSONAL / FAMILY HISTORY SUMMARY AND MANAGEMENT INFORMATION

RESULT: NEGATIVE / NO CLINICALLY SIGNIFICANT MUTATION IDENTIFIEDNote: “CLINICALLY SIGNIFICANT,” as defined in this report, is a genetic change that is associated with the potential to alter medical intervention.

ADDITIONAL FINDINGS: NO VARIANT(S) OF UNCERTAIN SIGNIFICANCE (VUS) IDENTIFIED

No clinically actionable mutations were identifi ed in this patient. However, based on personal/family history, the patient’s cancer risks may still be increased over the general population. Clinical management should be based upon personal and family history.

MODIFIED MEDICAL MANAGEMENT MAY BE APPROPRIATE

© 2014, Myriad Genetic Laboratories, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 800-469-7423 FX: 801-584-3615 myRisk Management Tool: Page 1 of 5

CONFIDENTIALCONFIDENTIAL



GENE MUTATION

BRCA1 c.68_69del (p.Glu23Valfs*17)

FAMILY MEMBER


AGE ATDIAGNOSIS

Patient None

Mother Breast 48-49†

Maternal Aunt Ovarian Not Provided

Paternal Uncle Prostate 50-59†

Maternal Cousin Lung Not Provided

This information was provided by a qualifi ed healthcare provider on the test request form and was not verifi ed by Myriad.† Age estimated based on information given. A more specifi c age may change cancer risk management suggestions provided.

THIS GENETIC TEST RESULT IS ASSOCIATED WITH THE FOLLOWING CANCER RISKS:

HIGH RISK: Female Breast, Ovarian

ELEVATED RISK: Pancreatic


Physician Name, MDMyriad Oncology Partners320 Wakara WaySalt Lake City, UT 84108

SPECIMEN

Specimen Type: BuccalDraw Date: Apr 8, 2012Accession Date: Apr 9, 2012Report Date: Apr 30, 2012

PATIENT

Name: Patient NameDate of Birth: Jan 12, 1950Patient ID: 1144Gender: FemaleAccession #: 00001144-BLDRequisition #: 000000ORDERING PHYSICIAN: Physician Name, MD




RESULT: POSITIVE—CLINICALLY SIGNIFICANT MUTATION IDENTIFIED

Note: “CLINICALLY SIGNIFICANT,” as defined in this report, is a genetic change that is associated with the potential to alter medical intervention.


NEGATIVE

ResultsSummary

PatientManagement

Tool

POSITIVE

Cancer Network (NCCN) recommend utilizing this 20%

threshold to target women for specific screening and risk

reduction interventions.**

There are special considerations for patients meeting cer-

tain personal and/or family history criteria associated with

colorectal cancer risk. Clinical information provided on the

TRF is analyzed to identify those patients whose families

meet the Amsterdam II Criteria for a suspected diagnosis of

Lynch syndrome, in which case there are detailed manage-

ment recommendations that should be considered. Analysis

of extended relatives may not be assessed for Amsterdam II

criteria due to limitations of understanding individual family

structure and relationship.

There are also recommendations for patients who have a

personal or family history of a first degree relative that have

10 or more adenomatous colorectal polyps. These patients

are possibly affected by either Familial Adenomatous Polyp-

osis (FAP) or Attenuated FAP (AFAP).

Cancer Risk ManagementThe clinical management guidelines provided on the myRisk

Management Tool are based on both a patient’s myRisk

Genetic Result and information about the patient’s personal

and family history as reported on the Test Request Form.

The clinical management recommendations summarized

on the myRisk Management Tool are primarily from NCCN

guidelines. In some cases, guidelines are from other expert

specialty groups or as outcomes from consensus confer-

ences, such as the International Gastric Cancer Linkage Con-

sortium (IGCLC) or the Cancer of the Pancreas Screening

Consortium (CAPS). In all cases, a reference is provided and

the reference should be consulted for details.

Providers may consider evaluating other patient factors with

risk models that are equivalently validated for breast cancer

(e.g., BRCAPro, BOADICEA, Tyrer-Cuzick). The components

of the medical management include:

• The use of interventions and/or screenings that would not

be recommended in the general population

• Initiating interventions and/or screenings at younger ages

• Conducting screenings more frequently

There are no cases where the recommendations provided in

connection with a clinically significant gene mutation, or a

family history, are meant to be less aggressive than those for

the general population.

While genetic testing and medical society guidelines provide

important and useful information, it is also important to take

into consideration aspects of the patient’s medical history,

lifestyle, environment and other factors in addition to the

myRisk Management Tool—for example, breast cancer risk

and management may be different based on past history of

breast biopsies, childbearing history, hormone replacement

therapy use, etc. Medical management decisions should be

made by the patient and their healthcare provider.

Patients with clinically significant mutations will receive

medical management information based primarily on an

identified gene mutation. If concerning family or personal

history and/or a lower penetrant mutation is also identified,

the most intensive management for the associated cancers

is provided.

The summary of medical management considerations pro-

vided on the myRisk Management Tool is meant to be a broad

overview, and is provided for informational purposes. Actual

care of the patient is the responsibility of the treating health-

care provider and should be based on a careful review of all

patient factors and consideration of the cited references and

other resources.

In many cases, patients with gene mutations detected with

Myriad myRisk or with unusually strong family history may

benefit from consultation with cancer genetics experts.

There are situations in which professional societies recom-

mend that care for specific conditions be coordinated by

centers with specialized expertise.



Patient Identification

Red Flags for Hereditary CancerAn individual with a personal or family history of any ONE of the following:

Based on professional guidelines, there is significant overlap

in identification criteria between multiple hereditary cancer

syndromes. While Myriad myRisk™ may make testing easier

by eliminating the need for matching a cancer phenotype

with test selection, it is very important that patients who may

benefit from testing are identified. One way to recognize

at-risk patients is with simple hereditary cancer red flags.

MULTIPLE: A combination of cancers on the same side of the family

• 2 or more: breast / ovarian / prostate / pancreatic cancer • 2 or more: colorectal / endometrial / ovarian / gastric / pancreatic / other

cancers (i.e., ureter/renal pelvis, biliary tract, small bowel, brain, sebaceous adenomas)

• 2 or more: melanoma / pancreatic cancer

YOUNG: Any 1 of the following cancers at age 50 or younger

• Breast cancer• Colorectal cancer• Endometrial cancer

RARE: Any 1 of these rare presentations at any age

• Ovarian cancer• Breast: male breast cancer or triple negative breast cancer• Colorectal cancer with abnormal MSI/IHC, MSI associated histology††

• Endometrial cancer with abnormal MSI/IHC• 10 or more gastrointestinal polyps*

††Presence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.*Adenomatous type.

Assessment criteria based on medical society guidelines. For these individual medical society guidelines, go to www.MyriadPro.com/guidelines. Family members include first-, second-, and third-degree blood relatives on both your mother and father’s sides.Certain ancestries may have greater risk for hereditary cancer syndromes (e.g., Ashkenazi Jewish ancestry).

†Abnormal MSI/IHC or histology.‡Male breast cancer, triple negative breast cancer.**Other Lynch syndrome-associated cancers, 10 or more gastrointestinal adenomatous polyps.§HBOC syndrome-associated cancers include breast (including ductal carcinoma in situ [DCIS]), ovarian, pancreatic, and aggressive prostate cancers.^ Lynch syndrome-associated cancers include colon/rectal, uterine/endometrial, ovarian, stomach/gastric, kidney/urinary tract, biliary tract, small bowel, pancreas, brain, and sebaceous adenoma cancers.

Hereditary Breast and Ovarian Cancer (HBOC)-associated cancers§

age 50 or younger any age2 or more

Lynch-associated cancers^

Breast

Prostate

Melanoma

Ovarian

Pancreatic

Colorectal

Endometrial

Gastric

Other**

RAREYOUNGMULTIPLE

Cancer risk and management analysis is based entirely on

what is reported by the healthcare provider on the Test

Request Form (TRF) submitted with the sample. If the clinical

history is not included or is missing information about the

relationship of family member, specific cancer diagnoses,

or specific ages at the time of diagnosis, Myriad myRisk

may not have sufficient information to provide professional

society based medical management recommendations.



Sample Submission

ORDERING PHYSICIAN SEND RESULTS TO (In addition to ORDERING PHYSICIAN)

NAME (LAST, FIRST, DEGREE) NPI # NAME (LAST, FIRST, DEGREE) NPI #

MYRIAD ACCOUNT NO: (If known) E-MAIL ADDRESS MYRIAD ACCOUNT NO: (If known) E-MAIL ADDRESS

ADDRESS CITY STATE ZIP ADDRESS CITY STATE ZIP

OFFICE CONTACT PHONE FAX OFFICE CONTACT PHONE FAX

PATIENT INFORMATION (COMPLETE INFORMATION REQUIRED FOR INSURANCE COVERAGE)PATIENT NAME (LAST, FIRST, INITIAL) PATIENT ID# BIRTH DATE (MM/DD/YYYY)

STREET ADDRESS CITY STATE ZIP DAYTIME PHONE NUMBER E-MAIL ADDRESS

ANCESTRY (Check all that apply)

WESTERN/NORTHERN EUROPE CENTRAL/EASTERN EUROPE AFRICA NEAR EAST/MIDDLE EAST OTHER ______________________________ ASHKENAZI LATIN AMERICA/CARIBBEAN ASIA NATIVE AMERICAN ______________________________________

FEMALE MALE

PATIENT PERSONAL HISTORY OF CANCER (Check all that apply)

FAMILY HISTORY OF CANCER Please list all family members with previous cancer/colorectal adenoma diagnoses. Please use one line per family member. Be complete and specific to optimize accuracy of patient's personalized Cancer Risk and Management Tool provided with test result. See back of form for detailed instructions.

NO KNOWN FAMILY HISTORY RELATIONSHIP MATERNAL PATERNAL CANCER SITE(s) (add # for COLON/RECTAL ADENOMA(s)) AGE(s) AT Dx

RELATIONSHIP MATERNAL PATERNAL CANCER SITE(s) (add # for COLON/RECTAL ADENOMA(s)) AGE(s) AT Dx

INFORMED CONSENT AND STATEMENT OF MEDICAL NECESSITYI affirm each of the following: I have provided genetic testing information to the patient and the patient has consented to genetic testing. This test is medically necessary for the diagnosis or detection of a disease, illness, impairment, symptom, syndrome or disorder. The results will be used in the patient's medical management and treatment decisions. The person listed as the Ordering Physician is authorized by law to order the test(s) requested herein. (NOTE: For Medicare patients, please complete the enclosed Informed Consent Form)(NOTE: Test requests without a signature will not be processed) MEDICAL PROFESSIONAL SIGNATURE DATE

OPTION 2: PATIENT PAYMENT Please call Customer Service for questions regarding test prices or for credit card payment.

OPTION 3: OTHER BILLING (To establish an account, submit billing information with this form)

SPECIMEN COLLECTION DATE (REQUIRED)MYRIAD GENETIC LABORATORIES, INC.A CLIA Certified Laboratory320 Wakara Way • Salt Lake City, Utah 84108(800) 469-7423 • (801) 584-1100Fax (801) 584-3615 • [email protected] NOTE: Af�x Bar Code Label to Specimen Tube

TESTS REQUESTED Integrated BRACAnalysis® with Myriad myRisk™ Hereditary Cancer – Analysis of BRCA1 and BRCA2 for susceptibility to Hereditary Breast and Ovarian Cancer syndrome with additional genes associated with hereditary cancer risk.

Multisite 3 BRACAnalysis – Three-mutation BRCA1 and BRCA2 analysis for individuals of Ashkenazi Jewish ancestry (187delAG, 5385insC, 6174delT). REFLEX to Integrated BRACAnalysis with Myriad myRisk Hereditary Cancer if the Multisite 3 is negative. Check here if a family member has tested positive for one of the above three mutations.

COLARIS®PLUS with Myriad myRisk Hereditary Cancer – Analysis of MLH1, MSH2, MSH6, PMS2, MUTYH, and EPCAM for susceptibility to Lynch syndrome, with additional genes associated with hereditary cancer risk. COLARIS AP ®PLUS with Myriad myRisk Hereditary Cancer – Analysis of APC for susceptibility to FAP/AFAP with additional genes associated with hereditary cancer risk. Single Site Testing (for family of known mutation carriers) Specify Gene:_____________________ and Mutation ______________________ Relationship: My patient is the _________________________ (e.g., maternal aunt) of the known mutation carrier. Required: Include a copy of the known mutation carrier’s report.

Myriad myRisk Update Test – Analysis of 25 hereditary cancer genes for patients who previously tested negative for BRACAnalysis, COLARIS, and/or COLARIS AP . Other: _________________________________________

BILLING/PAYMENT INFORMATION OPTION 1: PLEASE BILL MY INSURANCE (Option 1 requires patient signature and enlarged copy of both sides of insurance card(s). If two cards are submitted, indicate which is primary)

Name of Policy Holder: DOB: Insurance ID#: (Please attach copy of authorization/referral)Patient Relation to Policy Holder: Self Spouse Child Other Authorization/Referral #:

I represent that I am covered by insurance and authorize Myriad Genetic Laboratories, Inc. (MGL) to give my designated insurance carrier, health plan, or third party administrator (collectively "Plan") the information on this form and provided by my healthcare provider necessary for reimbursement. I authorize Plan benefits to be payable to MGL. I understand MGL will contact me prior to test start ONLY if my total financial responsibility will exceed $375 (for any reason, including co-insurance and deductible, or non-covered services). I agree to assist MGL in resolving insurance claim issues and if I don't assist, I may be responsible for the full test cost. I permit a copy of this authorization to be used in place of the original. I authorize MGL to inform my Plan of my relevant test result ONLY if it is negative and only if test results are required for preauthorization of or payment for reflex/additional testing.

REMINDER: INCLUDE A COPY OF BOTH SIDES OF

YOUR INSURANCE CARD(S)

Patient/Responsible Party Signature: Date:

Bill our institutional account #: or established research project code #: or Authorization/Voucher #:

NO PERSONAL HISTORY OF CANCER BREAST CANCER, Age at Dx:____________ Triple Negative (ER-, PR-, HER2-)

Ductal Invasive Lobular Invasive DCIS Bilateral Premenopausal ENDOMETRIAL/UTERINE CANCER, Age at Dx:____________ OVARIAN CANCER, Age at Dx:______________ Check here if non-epithelial OTHER CANCER(S): _________________________________ Age at Dx: ____________ OTHER CANCER(S): _________________________________ Age at Dx: ____________

COLON / RECTAL CANCER, Age at Dx:______________ TYPE (if known): Mucinous Signet Ring Medullary Growth Pattern

Tumor Infiltrating Lymphocytes Crohn's-like Lymphocytic Reaction COLON / RECTAL ADENOMAS, Age at Dx of First Adenomas:______________ CUMULATIVE #: 1 2-5 6-9 10-19 20-99 100+

PATIENT'S TUMOR IS MSI-HIGH OR IHC ABNORMAL (Result):___________________________ ≥5% ON A LYNCH SYNDROME RISK MODEL BONE MARROW TRANSPLANT RECIPIENT CURRENT DIAGNOSIS OF A HEMATOLOGIC CANCER

Myriad Hereditary Cancer TestsTest Request Form and Statement of Medical Necessity

TO AVOID DELAYS PLEASE COMPLETE ENTIRE FORM

This clinician will receive any test cancellation notices and the patient's copy of the test results.

myRiskHC/04-14 Myriad, the Myriad logo, Myriad myRisk Hereditary Cancer, BRACAnalysis, COLARIS and COLARIS AP are either trademarks or registered trademarks of Myriad Genetics, Inc., in the United States and other jurisdictions. ©2014

TESTS ORDERED WILL BE PROCESSED AND BILLED

BASED ON PAYOR CRITERIASAMP

LEPhysician, Bob, MD 345678901212345

Shirley Assistant 222-222-2222 222-222-2223

Doe, Jane T 00000 x 09/10/1954123 Generic Street �is City ST 45678 222-000-0000 [email protected]

X

X

X

X

X

XJane T. Doe 09/10/1954 ABC-123

SIGN & DATE

SIGN & DATE

07/25/2014

46

XAunt Breast 44

• Improved Screening(s) • Preventive Medication(s) • Considerations for Family

• Risk-Reducing Procedure(s) • Other Management Change

Average Turnaround Time:

• Results in 14 to 21 days

Myriad myRisk™ Report includes:

• myRisk Genetic Result

• myRisk Management Tool

- Guideline based (NCCN, Claus, CAPS, Amsterdam) cancer management for both positive and negative results

Completing the Test Request Form:

• Please include:

- Age and cancer diagnosis

- Gender and relationship

Cost: Myriad Promise™ • Vast majority of appropriate patients pay $0 • Myriad will work with your insurance to get

the appropriate coverage. We guarantee that we will work together to reach a solution.

Personalized Management of Cancer Risk May Include:

Genes & Associated Cancers* Br Ov Co En Me Pa Ga PrBRCA1, BRCA2 • • • • •MLH1, MSH2, MSH6, PMS2, EPCAM** • • • • •APC • • •MUTYH •CDK4, CDKN2A (p16INK4a, p14ARF) • •TP53 • • • • • • • •PTEN • • •STK11 • • • • • •CDH1 • • •BMPR1A, SMAD4 • • •PALB2, ATM • •CHEK2 • • •NBN • •BARD1 •BRIP1, RAD51C • •RAD51D •

1 Hereditary Cancer Red Flags • Multiple Cancers • Young Cancers • Rare Cancers/Presentations

General Population Familial Hereditary

ASSESSING CANCER RISK

Testing for Myriad myRisk™ Hereditary Cancer

TEST OVERVIEW

BENEFITS OF TESTING

COMMON QUESTIONS

2

3

4

Br - Breast / Ov - Ovarian / Co - Colorectal / En - Endometrial / Me - Melanoma / Pa - Pancreatic / Ga - Gastric / Pr - Prostate *Additional risks may be associated with each gene/syndrome. **Large rearrangement only.

For more information visit MySupport360.com and MyriadPro.com

Rights: Non-discrimination • Federal laws (HIPAA and GINA) and laws in most

states prohibit discrimination regarding employment eligibility, health benefits, or health insurance premiums based solely on genetic information.

myRisk Management Tool may not be reported without an accurate and specific personal and family history on this test request form

CANCER RISK

ORDERING PHYSICIAN SEND RESULTS TO (In addition to ORDERING PHYSICIAN)

NAME (LAST, FIRST, DEGREE) NPI # NAME (LAST, FIRST, DEGREE) NPI #

MYRIAD ACCOUNT NO: (If known) E-MAIL ADDRESS MYRIAD ACCOUNT NO: (If known) E-MAIL ADDRESS

ADDRESS CITY STATE ZIP ADDRESS CITY STATE ZIP

OFFICE CONTACT PHONE FAX OFFICE CONTACT PHONE FAX

PATIENT INFORMATION (COMPLETE INFORMATION REQUIRED FOR INSURANCE COVERAGE)PATIENT NAME (LAST, FIRST, INITIAL) PATIENT ID# BIRTH DATE (MM/DD/YYYY)

STREET ADDRESS CITY STATE ZIP DAYTIME PHONE NUMBER E-MAIL ADDRESS

ANCESTRY (Check all that apply)

WESTERN/NORTHERN EUROPE CENTRAL/EASTERN EUROPE AFRICA NEAR EAST/MIDDLE EAST OTHER ______________________________ ASHKENAZI LATIN AMERICA/CARIBBEAN ASIA NATIVE AMERICAN ______________________________________

FEMALE MALE

PATIENT PERSONAL HISTORY OF CANCER (Check all that apply)

FAMILY HISTORY OF CANCER Please list all family members with previous cancer/colorectal adenoma diagnoses. Please use one line per family member. Be complete and specific to optimize accuracy of patient's personalized Cancer Risk and Management Tool provided with test result. See back of form for detailed instructions.

NO KNOWN FAMILY HISTORY RELATIONSHIP MATERNAL PATERNAL CANCER SITE(s) (add # for COLON/RECTAL ADENOMA(s)) AGE(s) AT Dx

RELATIONSHIP MATERNAL PATERNAL CANCER SITE(s) (add # for COLON/RECTAL ADENOMA(s)) AGE(s) AT Dx

INFORMED CONSENT AND STATEMENT OF MEDICAL NECESSITYI affirm each of the following: I have provided genetic testing information to the patient and the patient has consented to genetic testing. This test is medically necessary for the diagnosis or detection of a disease, illness, impairment, symptom, syndrome or disorder. The results will be used in the patient's medical management and treatment decisions. The person listed as the Ordering Physician is authorized by law to order the test(s) requested herein. (NOTE: For Medicare patients, please complete the enclosed Informed Consent Form)(NOTE: Test requests without a signature will not be processed) MEDICAL PROFESSIONAL SIGNATURE DATE

OPTION 2: PATIENT PAYMENT Please call Customer Service for questions regarding test prices or for credit card payment.

OPTION 3: OTHER BILLING (To establish an account, submit billing information with this form)

SPECIMEN COLLECTION DATE (REQUIRED)MYRIAD GENETIC LABORATORIES, INC.A CLIA Certified Laboratory320 Wakara Way • Salt Lake City, Utah 84108(800) 469-7423 • (801) 584-1100Fax (801) 584-3615 • [email protected] NOTE: Af�x Bar Code Label to Specimen Tube

TESTS REQUESTED Integrated BRACAnalysis® with Myriad myRisk™ Hereditary Cancer – Analysis of BRCA1 and BRCA2 for susceptibility to Hereditary Breast and Ovarian Cancer syndrome with additional genes associated with hereditary cancer risk.

Multisite 3 BRACAnalysis – Three-mutation BRCA1 and BRCA2 analysis for individuals of Ashkenazi Jewish ancestry (187delAG, 5385insC, 6174delT). REFLEX to Integrated BRACAnalysis with Myriad myRisk Hereditary Cancer if the Multisite 3 is negative. Check here if a family member has tested positive for one of the above three mutations.

COLARIS®PLUS with Myriad myRisk Hereditary Cancer – Analysis of MLH1, MSH2, MSH6, PMS2, MUTYH, and EPCAM for susceptibility to Lynch syndrome, with additional genes associated with hereditary cancer risk. COLARIS AP ®PLUS with Myriad myRisk Hereditary Cancer – Analysis of APC for susceptibility to FAP/AFAP with additional genes associated with hereditary cancer risk. Single Site Testing (for family of known mutation carriers) Specify Gene:_____________________ and Mutation ______________________ Relationship: My patient is the _________________________ (e.g., maternal aunt) of the known mutation carrier. Required: Include a copy of the known mutation carrier’s report.

Myriad myRisk Update Test – Analysis of 25 hereditary cancer genes for patients who previously tested negative for BRACAnalysis, COLARIS, and/or COLARIS AP . Other: _________________________________________

BILLING/PAYMENT INFORMATION OPTION 1: PLEASE BILL MY INSURANCE (Option 1 requires patient signature and enlarged copy of both sides of insurance card(s). If two cards are submitted, indicate which is primary)

Name of Policy Holder: DOB: Insurance ID#: (Please attach copy of authorization/referral)Patient Relation to Policy Holder: Self Spouse Child Other Authorization/Referral #:

I represent that I am covered by insurance and authorize Myriad Genetic Laboratories, Inc. (MGL) to give my designated insurance carrier, health plan, or third party administrator (collectively "Plan") the information on this form and provided by my healthcare provider necessary for reimbursement. I authorize Plan benefits to be payable to MGL. I understand MGL will contact me prior to test start ONLY if my total financial responsibility will exceed $375 (for any reason, including co-insurance and deductible, or non-covered services). I agree to assist MGL in resolving insurance claim issues and if I don't assist, I may be responsible for the full test cost. I permit a copy of this authorization to be used in place of the original. I authorize MGL to inform my Plan of my relevant test result ONLY if it is negative and only if test results are required for preauthorization of or payment for reflex/additional testing.

REMINDER: INCLUDE A COPY OF BOTH SIDES OF

YOUR INSURANCE CARD(S)

Patient/Responsible Party Signature: Date:

Bill our institutional account #: or established research project code #: or Authorization/Voucher #:

NO PERSONAL HISTORY OF CANCER BREAST CANCER, Age at Dx:____________ Triple Negative (ER-, PR-, HER2-)

Ductal Invasive Lobular Invasive DCIS Bilateral Premenopausal ENDOMETRIAL/UTERINE CANCER, Age at Dx:____________ OVARIAN CANCER, Age at Dx:______________ Check here if non-epithelial OTHER CANCER(S): _________________________________ Age at Dx: ____________ OTHER CANCER(S): _________________________________ Age at Dx: ____________

COLON / RECTAL CANCER, Age at Dx:______________ TYPE (if known): Mucinous Signet Ring Medullary Growth Pattern

Tumor Infiltrating Lymphocytes Crohn's-like Lymphocytic Reaction COLON / RECTAL ADENOMAS, Age at Dx of First Adenomas:______________ CUMULATIVE #: 1 2-5 6-9 10-19 20-99 100+

PATIENT'S TUMOR IS MSI-HIGH OR IHC ABNORMAL (Result):___________________________ ≥5% ON A LYNCH SYNDROME RISK MODEL BONE MARROW TRANSPLANT RECIPIENT CURRENT DIAGNOSIS OF A HEMATOLOGIC CANCER

Myriad Hereditary Cancer TestsTest Request Form and Statement of Medical Necessity

TO AVOID DELAYS PLEASE COMPLETE ENTIRE FORM

This clinician will receive any test cancellation notices and the patient's copy of the test results.

myRiskHC/04-14 Myriad, the Myriad logo, Myriad myRisk Hereditary Cancer, BRACAnalysis, COLARIS and COLARIS AP are either trademarks or registered trademarks of Myriad Genetics, Inc., in the United States and other jurisdictions. ©2014

TESTS ORDERED WILL BE PROCESSED AND BILLED

BASED ON PAYOR CRITERIASAMP

LEPhysician, Bob, MD 345678901212345

Shirley Assistant 222-222-2222 222-222-2223

Doe, Jane T 00000 x 09/10/1954123 Generic Street �is City ST 45678 222-000-0000 [email protected]

X

X

X

X

X

XJane T. Doe 09/10/1954 ABC-123

SIGN & DATE

SIGN & DATE

07/25/2014

46

XAunt Breast 44

When filling out the personal and family history sections on the TRF, please include:

• Age of cancer diagnosis. Specific ages are preferred, but a range of <10 years (example: 60s) may be used

• Any diagnoses of cancer including colon/rectal adenomas, breast, colon/rectal, endometrial, melanoma, ovarian, pancreatic, prostate, renal pelvis, small bowel, gastric

• Patient gender

• “Maternal” or “Paternal” relationship

• All cancer types and corresponding ages for multiple primary cancers

• Specific count of cumulative adenomas (polyps)

Tests requested

• Select only the most appropriate test

• Complete all areas associated with the test specified

• Fill in ‘other’ for available test options not indicated on the TRF

The backside of the TRF provides discussion points, including:

• Cancer risk stratification

• Genes analyzed

• Test report and management expectations

• Frequently asked questions



Sample Submission

Myriad myRisk™ Test Kit Steps:

1. Complete the TEST REQUEST FORM.

2. Review INFORMED CONSENT with patient and have patient sign if appropriate.

3. Obtain COPIES OF INSURANCE CARDS.

4. Follow the COLLECTION INSTRUCTIONS [C] for collecting a sample.

5. Give the PATIENT GUIDE before mailing.

6. Lift the center tray of the test kit and follow the MAILING INSTRUCTIONS [E] underneath.

* Patients who have received a bone marrow transplant, or a recent chemotherapy regimen, or have a recent diagnosis for a hematological malignancy may not be suitable for Myriad myRisk testing. Please contact Myriad’s Professional Support Specialists prior to testing these individual cases.

If you have any questions about your sample submission, please call the Myriad Customer Service Department at 800-4-MYRIAD (800-469-7423).*Note: Immediately following blood collection ship the sample via FedEx. Samples can be held at ambient room temperature for up to 7 days prior to receipt at Myriad.

2. Place the 10 ml EDTA vial into the enclosed transportation tube with the absorbent strip. Place tube back into test kit box for shipping and continue following the steps printed on the left-hand panel of the box.

Following these instructions will avoid delays in the testing process. Test start will be delayed if the TEST REQUEST FORM is incomplete or the sample is improperly labeled.

A

1. Collect and label a 7 ml whole blood sample using the enclosed 10 ml EDTA vial. Complete the TRF and bar code label(s) with patient name and/or ID, date of birth, and specimen collection date. Peel label(s) off the TRF and place on the vial(s). MAKE SURE THE SAMPLE IS AT AMBIENT ROOM TEMPERATURE.*

C Blood Collection Instructions

Once the test kit is received, Myriad will automatically replenish your kit supply. If you would like to order additional tests or have any questions about your sample submission, please call the Myriad Customer Service Department at 800-4-MYRIAD (800-469-7423).

*It is the shipper’s responsibility to ensure that the package containing a diagnostic specimen conforms to FedEx guidelines along with all applicable local, state, federal and international regulations.

1. Remove the Myriad Clinical Pack Overwrap bag and mailing label.

4. If you don’t have a regularly scheduled FedEx pickup, call 800-GO-FEDEX (800-463-3339) to request one. Press “0” and specify that you are shipping with a prepaid air bill.

Please do not write the patient’s name on the test box.

Note: Immediately following specimen collection ship the sample via FedEx. Samples can be held at ambient room temperature for up to 7 days prior to receipt at Myriad.

2. Place signed TEST REQUEST FORM , INFORMED CONSENT FORM (required for Medicare patients), copies of insurance cards, and labeled and sealed collection tube into the box.

A

B

C

3. Close the box and place it into the Myriad Clinical Pack Overwrap bag, and affix the enclosed mailing label onto the front of the bag.*

E Mailing Instructions

Following these instructions will avoid delays in the testing process.

DO NOT EAT, DRINK OR CHEW GUM FOR 1 HOUR PRIOR TO SAMPLE COLLECTION

C Buccal (Oral Rinse)Collection Instructions SIDE 1

COMPLETELY FILL the

measuring cup with

mouthwash.

Spit ALL the mouthwash into

the collection tube.

Pour ALL the contents of cup

into your mouth and swish

vigorously for at least

30 seconds.

2 COLLECTION REQUIRED!

REPEAT above

steps (1 - 3),

adding to the

same collection

tube.

1.

3.

5.

2.

4. ND

Tube must be fi lled to at least the 20 ml line

Confi rm that the collection tube is FILLED TO AT LEAST THE 20 ML LINE.

Replace the red cap on the collection tube and screw on tightly to avoid spillage during shipping.

After 2nd collection, run tongue around your mouth, between your cheeks and gums, and spit out as much saliva as possible into collection tube. REPEAT ONE MORE TIME.

If you have any questions about your sample submission, please call the Myriad Customer Service Department at 800-4-MYRIAD (800-469-7423).*Note: Immediately following buccal collection ship the sample via FedEx. Samples can be held at ambient room temperature for up to 7 days prior to receipt at Myriad.

Patients who have received a Bone Marrow Transplant or Chemotherapy

regimen may not be suitable for the MyRisk Buccal test. Please contact the

Myriad Professional Support Specialists prior to testing.

Place labeled collection tube into the provided ziplock bag and seal the bag. Place bagged collection tube back into test kit box for shipping and proceed to Mailing Instructions.

SIDE 2

Test start will be delayed if the TEST REQUEST FORM is incomplete or the sample is improperly labeled.

A

C Buccal (Oral Rinse)Collection Instructions

6.

7.E

Complete the TRF and bar code label(s) with patient name and/or ID, date of birth, and specimen collection date. Peel label(s) off the TRF and place on the collection tube on top of the pre-printed white space. MAKE SURE THE SAMPLE IS AT AMBIENT ROOM TEMPERATURE.*



Cancer SiteOverviewGeneral Population



OverviewThe breast is mainly made up of three components: lob-

ules, ducts, and fatty tissue. Breast cancers that arise from

the epithelial cells lining these ducts and lobules are called

carcinomas and account for the majority of all breast can-

cer cases.

Carcinomas of the breast can be found to have either in-

vaded into surrounding tissues (invasive or infiltrating) or

not (in situ). In situ carcinomas, such as ductal carcinoma

in situ (DCIS), are treated very differently and much less

aggressively than its invasive counterpart. The most com-

mon breast cancer is the invasive ductal carcinoma and is

the focus of this document.

While the primary focus for breast cancer is on women,

men can get breast cancer as well. In 2013, there was an

estimated ~2200 new cases of invasive breast cancer ex-

pected in men in the US.

Signs and Symptoms4,5,6

Change in the look or feel of the breast or nipple; breast

lump or mass; swelling in all or part of the breast; skin

irritation or dimpling; breast or nipple pain; nipple retrac-

tion; redness, darkening, warm, scaliness, or thickening of

the nipple or breast skin; nipple discharge; swollen lymph

nodes under the arm or around the collar bone

Diagnosis and work-up

Screening Options4,5,6

Medical guidelines recommend those at general popula-

tion risk for breast cancer to have regular screening. Be-

ginning in the 20s, these include: clinical breast exam every

1-3 years, and self-awareness of breast changes. Beginning

at age 40-50 these include: annual clinical breast exams,

annual mammograms, self-awareness of breast changes.

For those at increased risk (e.g., >20% lifetime risk of

breast cancer), the following screening changes may be

warranted: clinical breast exams every 6-12 months, annual

mammograms and MRIs beginning at age 30 and consid-

eration of other risk reduction strategies. Individuals with

greater breast cancer risk may require a more intensive

medical management plan.

There are no screening recommendations for men at aver-

age-risk but breast self-exam, regular CBEs and mammog-

raphy screening (particularly in those with gynecomastia)

may be considered in men with increased risk.

Annual cases: ~232,0001

Median age at diagnosis: 611

Overall 5-year relative survival rate: 89.2%1

Lifetime risk in general population (female): 12.3%1

Risk with an affected 1st degree relative: 1.8-2.1x the general population risk2,3

Breast Cancer Fact Sheet General Population

69

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD51C

Pathology lab tests (ER,PR,HER2/neu) additional imaging for cancer spread

(bone scan, chest x-ray, MRI, CT, PET, US, etc.)

Medical history &

physical exam

Imaging tests (diagnostic mammograms,

MRI, ultrasound, etc.)

Biopsy (Fine needle aspiration biopsy,

core needle biopsy, surgery, etc.)



Treatment Options4,5,6

Early- advanced stage cancer

Treatment for small and localized breast tumors typically involve breast-conserving surgery where only the cancer and nearby tissues are removed (lumpectomy). This is often followed by lymph node dissection and/or therapy to reduce the risk of the cancer returning. More extensive surgery such as removing nearly all breast tissue (modified radical mastectomy) with or without breast recon-struction may be an option.

Radiation, chemotherapy with or without hormone therapy, hormone therapy alone, and/or targeted therapy can all be used as adjuvant treatments. Choices of therapy depend on individual factors such as the presence of hormone receptors. If the breast cancer is not immediate ly operable, neoadju-vant chemotherapy may be recommended.

Metastatic stagecancer

The primary treatment is with systemic therapy, which may include hormone therapy, chemotherapy, targeted therapies, and/or some combination of these treatments. Palli-ative interventions are often used in patients with metastatic cancers in order to prevent/relieve symptoms.

Risk Factors4,5,6 Demographics: Older age; female gender

Lifestyle: Obesity; alcohol consumption; physical inactivity

Medical history: Previous history of breast cancer, LCIS,

proliferative breast conditions with or without atypia;

dense breast tissue; post-menopausal estrogen and pro-

gesterone hormone therapy; previous chest wall radiation

exposure; diethylstilbestrol (DES) exposure; nulliparity;

age of first pregnancy >30 years

Risk reduction options: Multiple pregnancies; pregnancy

<age 30; breastfeeding; physical activity; preventive mas-

tectomy; pre-menopausal oophorectomy; chemopreven-

tive drugs such as Tamoxifen and Raloxifene

Inherited: Family history of disease; inherited genetic syn-

dromes

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD51C

REFERENCES: 1. Surveillance, Epidemiology and End Results Program, National Cancer Institute (seer.cancer.gov) Dec 10, 2013.

2. Pharoah PD, Day NE, Duffy S, Easton DF, Ponder BA. Family history and the risk of breast cancer: a systematic review and meta-analysis. Int J Cancer. 1997 May 29;71(5):800-9. PubMed PMID: 9180149.

3. Collaborative Group on Hormonal Factors in Breast Cancer. Familial breast cancer: collaborative reanalysis of individual data from 52 ep-idemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet. 2001 Oct 27;358(9291):1389-99. Review. PubMed PMID: 11705483.

4. American Society of Clinical Oncology: Breast Cancer (http://www.cancer.net/cancer-types/breast-cancer) Dec 10, 2013.

5. American Cancer Society: Breast Cancer (http://www.cancer.org/can-cer/breastcancer/index) Dec 10, 2013.

6. National Cancer Institute: Breast Cancer treatment (http://www.cancer.gov/cancertopics/pdq/treatment/breast/patient) Dec 10, 2013.

7. Bevers TB et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013

Stage IIIB Breast Cancer



OverviewThe ovaries are small, paired female reproductive glands

that serve as the main source of the hormones estrogen

and progesterone. Ovarian cancer is cancer that begins in

the ovaries and may arise from 3 main kinds of cells: epi-

thelial cells (cells that cover the ovaries), germ cells (cells

that produce the eggs) and stromal cells (cells that form

the supporting or structural tissue holding the ovaries to-

gether).

Ovarian carcinomas are the most common ovarian can-

cers, accounting for about 85% to 90% of all ovarian can-

cers. Subtypes include serous, mucinous, endometrioid,

clear cell and undifferentiated. The main focus of this doc-

ument is epithelial ovarian carcinomas.

Ovarian cancer often goes undetected. Often the cancer is

found after it has spread within the pelvis and abdomen.

As a result the cancer is difficult to treat.

Fallopian tube and primary peritoneal cancer are closely

related to epithelial ovarian cancer.


Poor appetite; weight loss; abdominal pain or vague dis-

comfort above navel; sense of fullness in upper abdomen

after eating a small meal; heartburn or indigestion; nausea;

vomiting (+/- blood); swelling or fluid build-up in abdo-

men.



There are no screening test recommendations for ovari-

an cancer at this time. Transvaginal ultrasonography and

CA–125 testing may be suggested when appropriate.


Early stage cancer

Surgery to remove the tumor is the primary treatment. The grade of the cancer, which determines aggressiveness, may suggest watchful surveillance or treatment with che-motherapy after surgery.




Lifetime risk in general population: 1.4%1


Ovarian Cancer Fact Sheet General Population

69

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, STK11, BRIP1, RAD51C, RAD51D

Surgery for staging, sampling and/or excision

Medical history &

physical exam

Pelvic exam and blood work (CA-125, liver and

kidney function test, etc.)

Imaging tests (transvaginal or abdominal

ultrasounds, MRI, PET, CT, etc.)



Advancedstage cancer

Surgery for staging and debulking the cancer is generally indicated. This includes removal of the uterus along with the fallopian tubes and ovaries (total abdominal hysterectomy with bilateral salpingo-oophorectomy). In addition, the omentum, fluid in the pelvis or abdominal cavity, and lymph nodes in the pelvis and abdomen are removed and ana-lyzed. Chemotherapy is recommended for at least 6 cycles.

Metastatic stage cancer

Treatment options include surgery and combination chemotherapy, which involve more than one medication at a time. Differ-ent options of administrating chemotherapy, such as intraperitoneal chemotherapy, may be suggested. Patients who are too weak to have full staging and debulking surgery are sometimes treated with chemotherapy as the first treatment. Clinical trials for combination chemotherapy, biologic therapy and/or tar-geted therapy may be considerations.

Risk Factors4,5,6 Demographics: Older age

Lifestyle: Smoking

Medical history: Early menarche/late menopause, obesity,

fertility drugs; estrogen hormonal therapy

Risk reduction options: Birth control pills; injectable hor-

monal contraceptives; pregnancy; breastfeeding; tubal

ligation; hysterectomy; bilateral salpingo-oophorectomy;

other contraception that prevents ovulation; low-fat diet


dromes

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, STK11, BRIP1, RAD51C, RAD51D


2. Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst. 1994 Nov 2;86(21):1600-8. PubMed PMID: 7932824.

3. Stratton JF, Pharoah P, Smith SK, Easton D, Ponder BA. A systematic review and meta-analysis of family history and risk of ovarian cancer. Br J Obstet Gynaecol. 1998;105(5):493–499.

4. American Society of Clinical Oncology: Ovarian Cancer (http://www.cancer.net/cancer-types/ovarian-cancer) Dec 10, 2013.

5. American Cancer Society: Ovarian Cancer (http://www.cancer.org/cancer/ovariancancer/index) Dec 10, 2013.

6. National Cancer Institute: Ovarian Cancer treatment (http://www.can-cer.gov/cancertopics/pdq/treatment/Ovarian/patient) Dec 10, 2013.

Stage IIB and IIC Ovarian Cancer



OverviewGastric cancer (stomach cancer) is a cancer that starts

in the stomach. The stomach has 5 parts: cardia; fun-

dus; body (corpus); antrum; pylorus. Cancers starting in

different sections of the stomach tend to have different

symptoms, outcomes and treatment options. Most gastric

cancers start in the top mucosal layer and as the cancer

grows into the deeper layers, the stage is more advanced

and the prognosis is not as good.

This summary focuses on the most common type called

gastric adenocarcinoma. Gastric adenocarcinomas are

classified histologically into intestinal or diffuse sub-types.


Poor appetite; weight loss; abdominal pain or vague dis-

comfort above navel; sense of fullness in upper abdomen

after eating a small meal; heartburn or indigestion; nausea;

vomiting (+/- blood); swelling or fluid build-up in abdo-

men.



In the U.S., there is no standard or routine screening test

for gastric cancer; the effectiveness of current screening

techniques for the early diagnosis of gastric cancer is not

proven. For those at elevated or high risk, screening may

include upper endoscopy and/or capsule endoscopy at

regular intervals, with random and targeted biopsies as

indicated.

Most gastric cancers are adenocarcinomas

Adenocarcinomas Other types • 90-95% • 5-10%






Gastric Cancer Fact Sheet General Population

Associated Myriad myRisk™ Genes: MLH1, MSH2, MSH6, PMS2, EPCAM, APC, TP53, STK11, CDH1, BMPR1A, SMAD4

69

Blood tests (CBC, liver function,

tumor markers, etc.)

Fecal Occult Blood

Test (FOBT)

Medical history &

physical exam

Upper GI endoscopy & biopsy

Imaging tests (MRI, CT, PET, U/S, x-rays, etc.)

for cancer spread




Early stagecancer

Surgery is typically used to remove the part of the stomach with cancer (gastrectomy) and nearby lymph nodes.

Advancedstagecancer

Surgery removing a part or the entire stom-ach (gastrectomy) as well as surrounding tissues, organs, and lymph nodes may be used plus adjuvant and/or neoadjuvant che-motherapy and/or radiation therapy.


Often treated with chemotherapy. Targeted therapy in combination with chemotherapy may be used to treat HER2-positive met-astatic gastric cancers. Palliative surgeries may be performed for unresectable cancers to control growth or to prevent or relieve symptoms and/or complications.

Risk Factors3,4,5 Demographics: Older age; male gender; ethnicity – His-

panic/Latino, African, Asian

Lifestyle: Diet high in salt and smoked food; tobacco use;

low intake of fruits & vegetables; obesity; occupational

exposures

Medical history: H. pylori; chronic gastritis; stomach pol-

yps; previous stomach surgery; stomach lymphoma; perni-

cious anemia; common immune deficiency syndrome

Risk reduction options: Prophylactic gastrectomy (typ-

ically only considered for high risk individuals); healthy

diet; physical activity; nonsteroidal anti-inflammatory

drugs (NSAIDS)

Inherited: Type A blood; family history of disease; inher-

ited genetic syndromes

Associated Myriad myRisk™ Genes: MLH1, MSH2, MSH6, PMS2, EPCAM, APC, TP53, STK11, CDH1, BMPR1A, & SMAD4


2. Yaghoobi M, Bijarchi R, Narod SA. Family history and the risk of gastric cancer. Br J Cancer. 2010 Jan 19;102(2):237-42. doi: 10.1038/sj.bjc.6605380. Epub 2009 Nov 3. PubMed PMID: 19888225; PubMed Central PMCID: PMC2816643.

3. American Society of Clinical Oncology: Gastric Cancer (http://www.cancer.net/cancer-types/stomach-cancer) Dec 10, 2013.

4. American Cancer Society: Gastric Cancer (http://www.cancer.org/can-cer/stomachcancer/index) Dec 10, 2013.

5. National Cancer Institute: Gastric Cancer treatment (http://www.can-cer.gov/cancertopics/pdq/treatment/gastric/Patient) Dec 10, 2013.

Gastric Cancer



OverviewThe colon and rectum can be found between the small in-

testines and the anus in the digestive system. The colon

consists of 4 sections (from nearest to and furthest from

the small intestines): ascending colon, transverse colon,

descending colon and sigmoid colon.

Colorectal cancer starts in the colon or the rectum and

have many features in common. Colorectal cancer gener-

ally develops slowly from a non-cancerous polyp on the

inner lining of the colon/rectum. Of the different types

of polyps, most cancers arise from adenomatous polyps

(adenomas). Other colorectal polyps such as hyperplas-

tic polyps and inflammatory polyps, in general, are not

pre-cancerous but may be a sign of greater risk to develop

adenomas and colorectal cancer.

More than 95% of colorectal cancers are adenocarcinomas,

which arise from adenomas. There are other less common

colorectal tumors but the focus for this document is on

adenocarcinoma of the colon and rectum.


A change in bowel habits that lasts for more than a few

days; diarrhea or constipation; narrowing of the stool;

feeling that the bowel does not empty completely; rectal

bleeding, dark stools, or blood in the stool; cramping or

abdominal pain or discomfort; weakness and fatigue; un-

intended weight loss; unexplained iron-deficiency anemia.


Screening Options6

For average-risk individuals, routine colonoscopies every

10 years, or flexible sigmoidoscopies every 5 years start-

ing at age 50, is recommended unless otherwise indicat-

ed by findings. Alternatives include annual FOBT or FIT

stool testing with or without flexible sigmoidoscopy every

5-10 years, CT-colonography every 5 years, double-con-

trast barium enema every 5 years, or flexible sigmoidos-

copy alone. Screening for those at increased risk, including

those with a history of polyps, may involve more frequent

colonoscopy screening beginning at an age earlier than 50.





Risk with an affected 1st degree relative: 2.3x the general population risk2

Colorectal Cancer Fact Sheet General Population

69

Associated Myriad myRisk™ Genes: MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, TP53,

PTEN, STK11, CDH1, BMPR1A, SMAD4, CHEK2

Tests on Tumor Sample (routine histopathology tests, microsatellite instability, etc.)

Imaging tests (MRI, CT, PET, U/S, x-rays,

etc.) for cancer spread

Medical history &

physical exam

Stool & Blood Tests (FOBT; CBC, liver & kidney

function, CEA tumor marker)

GI endoscopy & biopsy (Colonoscopy with biopsy, Rigid

Protoscopy in rectal cancer)




Early stage cancer

Surgery is typically used to remove the part of the colon with cancer and nearby lymph nodes. If the cancer is found at a very early stage, a local excision, where the cancer is re-moved without cutting through the abdominal wall, may be performed. Otherwise, resection (removing a section of the affected colon) and anastomosis (connecting the resected ends) may be considered.

Advancedstage cancer

How much colon is removed differs between individuals and is based on the aggressiveness and location of the cancer and how high risk the patient is for second primary tumors.

Surgery removing a part or the entire colon (resection and anastomosis) as well as sur-rounding tissues, affected organs, and lymph nodes may be performed, followed by adju-vant chemotherapy.

The surgical approach to rectal cancer differs from that of colon cancer, because issues related to maintaining or restoring normal anal sphincter, genitourinary, and sexual functions need to be considered.

Radiation therapy is often used in combination with chemotherapy to treat rectal cancer.


After surgical resection on affected organs, if feasible, chemotherapy, targeted therapy and/or radiation therapy may be used to treat metastases. Palliative surgeries may be performed for unresectable cancers to control growth or to prevent or relieve symptoms/complications.

Risk Factors3,4,5 Demographics: Older age, ethnicity – African, Ashkenazi

Jewish

Lifestyle: Diet high in red meats and processed meats; to-

bacco use; low intake of fruits & vegetables; obesity; phys-

ical inactivity; heavy alcohol use

Medical history: History of adenomatous polyps or col-

orectal cancer diagnosis; chronic inflammatory bowel dis-

ease; type 2 diabetes; radiation exposure

Risk reduction options: Healthy diet; physical activity;

long-term regular nonsteroidal anti-inflammatory drugs

(NSAIDS) use; routine screening and removal of polyps

Inherited: Family history of polyps or colorectal cancer di-

agnosis; inherited genetic syndromes

Associated Myriad myRisk™ Genes: MLH1, MSH2, MSH6, PMS2, EPCAM, APC, MUTYH, TP53, PTEN, STK11, CDH1, BM-PR1A, SMAD4 and CHEK2

REFERENCES:1. Surveillance, Epidemiology and End Results Program, National Cancer Institute (seer.cancer.gov) Dec 10, 2013.

2. Johns LE, Houlston RS. A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol. 2001 Oct;96(10):2992-3003. Review. PubMed PMID: 11693338.

3. American Society of Clinical Oncology: Colon Cancer (http://www.can-cer.net/cancer-types/colon-cancer) Dec 10, 2013.

4. American Cancer Society: Colon Cancer (http://www.cancer.org/can-cer/coloncancer/index) Dec 10, 2013.

5. National Cancer Institute: Colon Cancer treatment (http://www.cancer.gov/cancertopics/pdq/treatment/colon/Patient) Dec 10, 2013.

6. Burt RW et al. NCCN Clinical Practice Guidelines in OncologyR Col-orectal Cancer Screening. V 2.2013

Stage I Colorectal Cancer



OverviewThe pancreas is an organ located behind the stomach and

has 3 parts: the head, body, and tail. It contains 2 types of

glands. The endocrine glands produce hormones such as

insulin and glucagon. The exocrine glands make enzymes

used to digest food.

There are several types of pancreatic tumors. Cancers

arising in the exocrine pancreas are more common than

cancers arising in the endocrine pancreas. This summary

focuses on pancreatic exocrine cancers.

Another type of cancer, called ampullary cancer, is a can-

cer that starts near the pancreas. Ampullary cancers are

often considered like exocrine pancreatic cancers because

the treatments are similar.


Jaundice; abdominal or back pain; weight loss; poor ap-

petite; digestive problems; gallbladder enlargement; blood

clots or fatty tissue abnormalities; diabetes.



There are no standard or routine screening tests for pan-

creatic cancer; the effectiveness of current screening

techniques for the early diagnosis of pancreatic cancer

has not been proven. For those at elevated or high risk,

available screening options may include endoscopic ultra-

sound (EUS), MRI/magnetic resonance cholangiopancrea-

tography (MRCP) and use of CA19-9 blood tumor marker

tests at regular intervals. It is recommended that patients

who are candidates for pancreatic cancer screening be

managed by a multidisciplinary team with experience in

pancreatic cancer screening, preferably within research

protocols.

Most pancreatic cancers arise in the exocrine

Exocrine tumors Other types • ~95% • ~5%






Pancreatic Cancer Fact Sheet General Population

69

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, CDKN2A (p16INK4a),

CDKN2A (p14ARF), CDK4, TP53, STK11, BMPR1A, SMAD4, PALB2, ATM

Tissue tests (CT-guided needle biopsy, EUS- or CT-fine

needle aspiration, surgical biopsy)

Blood tests (CBC counts, liver & kidney function

tests, bilirubin, CA19-9, CEA, etc.)

Medical history &

physical exam

Imaging Scans (specialized pancreatic CT or MRI,

PET/CT, abdominal ultrasound, etc.)

Scopes (endoscopic ultrasound , endoscopic

retrograde cholangiopancreatograph)





Surgical resection is considered the only potentially curative technique for managing pancreatic cancer. However, most pancreatic cancers cannot be treated with surgery. Sur-gically resectable and potentially resectable pancreatic cancers are those found just in the pancreas or have only spread just outside the pancreas but not into nearby major blood vessels. Surgical resection involves removing part or all of the pancreas as well as nearby organs, ducts, blood vessels, and lymph nodes depending upon the location of the tumor in the pancreas. This is often then followed by chemotherapy and in some cases radiation therapy. Unresectable cancers that have not yet spread to distant organs but still cannot be removed with surgery are often treated with chemotherapy or sometimes chemotherapy with radiation.


Metastatic pancreatic cancer is most often managed with chemotherapy, sometimes in combination with targeted therapy. Palliative interventions are often used in patients with unresectable or metastatic cancers in order to prevent/relieve symptoms or fix problems like a blocked bile duct. Pain control is often an important part of treatment for many patients as well as therapy to manage nutri-tional deficiencies. Many patients choose to participate in clinical trials investigating novel treatment approaches.

Risk Factors3,4,5 Demographics: Older age

Lifestyle: Diet high in fats and meats; obesity; tobacco use;

alcohol use; occupational exposures

Medical history: Chronic pancreatitis; cirrhosis of the liver;

type 2 diabetes; H. Pylori stomach infection

Risk reduction options: Maintain diet low in fats/meats;

physical activity; avoiding tobacco use; limiting alcoholic

beverages; treating H. Pylori stomach infections


dromes

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS2, EPCAM, APC, CDKN2A (p16INK4a), CDKN2A (p14ARF), CDK4, TP53, STK11, BMPR1A, SMAD4, PALB2, ATM


2. Tersmette AC, Petersen GM, Offerhaus GJ, Falatko FC, Brune KA, Gog-gins M, Rozenblum E, Wilentz RE, Yeo CJ, Cameron JL, Kern SE, Hruban RH. Increased risk of incident pancreatic cancer among first-degree rel-atives of patients with familial pancreatic cancer. Clin Cancer Res. 2001 Mar;7(3):738-44. PubMed PMID: 11297271.

3. American Society of Clinical Oncology: Pancreatic Cancer (http://www.cancer.net/cancer-types/pancreatic-cancer) Dec 10, 2013.

4. American Cancer Society: Pancreatic Cancer (http://www.cancer.org/cancer/pancreaticcancer/index) Dec 10, 2013.

5. National Cancer Institute: Pancreatic cancer treatment (http://www.can-cer.gov/cancertopics/pdq/treatment/pancreatic/Patient) Dec 10, 2013.

Stage IIA Pancreatic Cancer



OverviewMelanoma is a type of skin cancer that starts in mela-

nocytes, which are cells found in the outermost layer of

skin (the epidermis). Melanocytes make a brown pigment

called melanin. Melanin protects the deeper layers of skin

(the dermis and subcutis layers) from the harmful effects

of the sun.

When skin cancer becomes more advanced, it general-

ly grows through this barrier and into the deeper layers

where lymph and blood vessels are present. Compared

to other skin cancers, melanoma is considered much less

common but far more dangerous because it is more likely

to spread into the deeper skin layers and metastasize.

Because most melanomas still make melanin, melanoma

tumors are usually black or brown. However some mela-

nomas do not make melanin and can appear pink, tan, or

white. Melanomas can appear anywhere on the skin but

are more likely to start in certain locations like the chest

and back in men, the legs in women, or on the neck and

face. Melanomas can also form in other parts of the body

in mucosal tissue like in the eyes, mouth, and genitals but

these are much less common than cutaneous melanomas.

The focus for this overview is cutaneous melanoma.

Cutaneous melanomas are categorized into 4 main types:

superficial spreading melanoma (the most common), nod-

ular, lentigo maligna, and acral lentiginous melanomas.


Moles meeting the ABCDE rule (asymmetry, irregular bor-

ders, inconsistent color, diameter larger than the size of

a pencil, evolving color, shape or size); a sore that does

not heal; spread of pigment from the border of a spot to

surrounding skin; redness or a new swelling beyond a mole

border; a change in sensation—itchiness, tenderness or

pain; change in the surface of a mole—scaliness, oozing,

bleeding, or appearance of a bump or nodule.


Blood tests (CBC, blood chemistry tests, liver and kidney

function tests, LDH tumor marker levels) and other imag-

ing tests (chest X-ray, CT scan, CT-guided needle biopsy,

MRI, PET scan) may also be ordered as part of the staging

process and to plan treatment.






Melanoma Cancer Fact Sheet General Population

69

Associated Myriad myRisk™ Genes: BRCA2, CDKN2A (p16INK4a), CDKN2A (p14ARF), CDK4, TP53

Lab tests of biopsy sample (Breslow thickness, ulceration status, mitotic rate,

BRAF gene analysis if advanced disease, etc.)

Medical history &

physical exam

Imaging(dermatoscopy and/or digital

images or photographs)

Skin biopsy (shave, punch, incisional or excisional),

& possible lymph node biopsy




For patients who present with one or more signs or symp-

toms, a clinical exam is typically performed and may

include the use of dermoscopy and digital images or pho-

tographs to better examine the suspected spot.


Early- advanced stagecancer

The primary treatment for early stage melanoma is wide surgical excision. Adju-vant therapy in the form of immunotherapy injections, radiation therapy, and/or chemo-therapy may be given after surgery if there is thought to be a high risk of recurrence.

For regional melanomas, wide excision and a lymph node dissection is often performed plus possible adjuvant therapy.

If surgery cannot remove the entire tumor, other local treatments like immunotherapy injections or creams, ablation therapy, che-motherapy (local or systemic), or radiation therapy may be used instead for primary treatment.


Surgery is often possible and may be fol-lowed with entry into a clinical trial. Dis-seminated metastatic melanoma is typically treated with systemic therapy and may include chemotherapy, immunotherapy, and/or targeted therapy; if brain metastases are present, palliative surgery and/or radiation therapy is usually done first to prevent or ease CNS symptoms.

Risk Factors3,4,5 Demographics: Older age; male gender; ethnicity—Cau-

casian

Lifestyle: UV light exposure

Medical history: Dysplastic nevi; previous melanoma his-

tory; immune suppression; moles, congenital melanocytic

nevi; fair complexion

Risk reduction options: Limit UV exposure; self-skin aware-

ness; removal of abnormal moles

Inherited: Moles; congenital melanocytic nevi; fair com-

plexion; family history of disease; inherited genetic syn-

dromes

Associated Myriad myRisk™ Genes: BRCA2, CDKN2A (p16INK4a), CDKN2A (p14ARF), CDK4, TP53



3. American Society of Clinical Oncology: Melanoma (http://www.cancer.net/cancer-types/melanoma) Dec 10, 2013.

4. American Cancer Society: Skin Cancer – Melanoma (http://www.cancer.org/cancer/skincancer-melanoma/index) Dec 10, 2013.

5. National Cancer Institute: Melanoma treatment (http://www.cancer.gov/cancertopics/pdq/treatment/melanoma/Patient) Dec 10, 2013.

Stage III Melanoma



OverviewThe prostate is a walnut sized reproductive gland in males.

It is located below the bladder and in front of the rectum.

The focus of this document is on prostate adenocarci-

noma, which accounts for 95% of all prostate cancers.

Other types of prostate cancer include sarcomas, small cell

carcinomas, and transitional cell carcinomas.

Compared to many other cancers, prostate cancer tends

to grow slowly. Consequently, many men with prostate

cancer may die of some other cause before the prostate

cancer causes any symptoms. However, some prostate

cancers do grow rapidly and can potentially impact sur-

vival and quality of life.


Early prostate cancer usually causes no symptoms. Signs

and symptoms of advanced prostate cancer may include:

frequency urination; weak or interrupted urine flow; loss

of bladder or bowel control; blood in the urine or seminal

fluid; impotence; discomfort when sitting; pain in the back,

hips, thighs, chest, shoulders or other bones; weakness

or numbness in the legs or feet; unexplained weight loss;

fatigue; high PSA levels (PSA: a protein produced by pros-

tate cells).


Screening Options7

Medical guidelines recommend the general population

with average risk of prostate cancer to begin risk and ben-

efit discussion with their providers about baseline digital

rectal examination (DRE) and PSA at age 40.




Lifetime risk in general population: 15.3% in men1


Prostate Cancer Fact Sheet General Population

69

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, TP53, CHEK2, NBN

Lab tests and imaging Pathology lab tests (Gleason score); PSA serum level monitoring;

Imaging tests (bone scans, MRI, CT, PET, etc.) for cancer spread

Medical history &

physical exam

Screening test Digital Rectal Exam (DRE) and Prostate

Specific Antigen (PSA) exam

Tissue sampling Biopsy or extraction during transurethral

resection or radical prostatectomy

Most prostate cancers are adenocarcinoma

Prostate adenocarcinoma Other types • ~95% • ~5%





Because of the slow-growing nature of many prostate cancers as well as the side effects associated with treating prostate cancer, the type of treatment used should take into ac-count many individual factors, including age, life expectancy, cancer stage & grade, and other medical conditions. Active surveillance for any sign that the cancer may be growing or changing may be an option for early stage prostate cancer. This will entail frequent doc-tor visits and tests, such as DRE, PSA tests, and biopsies.

The most common treatment for prostate cancer is a prostatectomy – a surgery to remove the cancerous prostate from the body. Lymph nodes from the pelvis may be removed for analysis. Surgery is generally recommended for men with early stage or low-grade cancers but is sometimes used at advanced stages to relieve symptoms. Radi-ation therapy and hormonal therapy may be used as neoadjuvant or adjuvant therapy for better outcome.

Localized low grade prostate cancer may benefit from radiation therapy with hormonal therapy as the primary treatment.


If the cancer has spread, hormonal therapy and other methods may be suggested to slow cancer growth and alleviate symptoms. If standard treatments are not effective, che-motherapy and clinical trials may be options.

Risk Factors4,5,6 Demographics: Older age; ethnicity—African-American

Lifestyle: : Diet high in red meat & high-fat dairy

Medical history: High levels of androgen hormones, high-

grade PIN, proliferative inflammatory atrophy

Risk reduction options: Healthy lifestyle


dromes

Associated Myriad myRisk™ Genes: BRCA1, BRCA2, TP53, CHEK2, NBN



3. Kicinski M, Vangronsveld J, Nawrot TS. An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PLoS One. 2011;6(10):e27130. doi: 10.1371/journal.pone.0027130. Epub 2011 Oct 31. PubMed PMID: 22073129; PubMed Central PMCID: PMC3205054.

4. American Society of Clinical Oncology: Prostate Cancer (http://www.cancer.net/cancer-types/prostate-cancer) Dec 10, 2013.

5. American Cancer Society: Prostate Cancer (http://www.cancer.org/cancer/prostatecancer/index) Dec 10, 2013.

6. National Cancer Institute: Prostate treatment (http://www.cancer.gov/cancertopics/pdq/treatment/prostate/Patient) Dec 10, 2013.

7. Presti, JC et al. NCCN Clinical Practice Guidelines in OncologyR: Pros-tate Cancer Early Detection. Version 1.2014.

Stage I Prostate Cancer



OverviewThe uterus consists of 2 main layers: the endometrium (in-

ner layer) and the myometrium (outer layer).

Most cancers of the uterus are from cells that form glands

in the endometrium layer and are called endometrial carci-

nomas. The focus of this document is on the most common

type of endometrial carcinoma, known as endometrioid

adenocarcinoma. More aggressive forms include clear-cell,

serous and poorly differentiated carcinoma.

Endometrial cancer is often mistaken for but is not the

same as cervical cancer, which starts in the cervix and may

spread to the body of the uterus.


Unusual vaginal bleeding, spotting and/or abnormal dis-

charge; difficulty or pain when urinating; pain during sex-

ual intercourse; abdominal fullness/pressure; pelvic pain;

pelvic mass; weight loss.



There are no regular screening test recommendations for

endometrial cancer at this time. In most cases, endometrial

cancers are found by noticing related signs and symptoms,

which is followed up by examination. For those at elevated

or high risk, screening may include endometrial biopsies

and/or transvaginal ultrasounds at regular intervals.






Endometrial Cancer Fact Sheet General Population

69

Associated Myriad myRisk™ Genes: MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, PTEN, STK11

Lab tests and imaging Pathology lab tests of sample; cystoscopy and proctoscopy and

imaging (ultrasounds, PET, MRI, CT, etc.) for cancer spread

Medical history &

physical exam

Screening test Pelvic exam and transvaginal

ultrasound (TVUS)

Tissue sampling Endometrial biopsy or dilation and curettage (D&C)

with or without a hysteroscopy for endometrial tissue




Early- advanced stagecancer

The primary treatment for early stage endometrial cancer is surgery which may entail removal of the uterus (hysterecto-my) or removal of the uterus along with the fallopian tubes and ovaries (total abdominal hysterectomy with bilateral salpingo-oopho-rectomy). Lymph nodes from the pelvis and along the aorta may also be removed and analyzed. Other therapies, including vaginal brachytherapy (VB), pelvic radiation, or both may be recommended either before or after surgery.

If the endometrial cancer is aggressive and/or of high grade, the surgery may be more extensive including removal of the omentum. Chemotherapy is often given along with radiation therapy.


Surgery may be appropriate to alleviate symptoms. Disseminated metastatic endo-metrial is typically treated with chemother-apy and radiation therapy and/or hormonal therapy.

Risk Factors4,5,6 Demographics: Older age; female gender

Lifestyle: High fat diet; obesity

Medical history: Estrogen-only hormone replacement

therapy; Tamoxifen use; other causes of excess exposure to

estrogen unopposed by progesterone; polycystic ovarian

syndrome (PCOS); diabetes; endometrial hyperplasia;

prior radiation exposure; nulliparity; early menarche and

late menopause; infertility; prior pelvic radiation therapy

Risk reduction options: Birth control pills; hysterectomy

and bilateral salpingo-oophorectomy; pregnancy; physical

activity


dromes

Associated Myriad myRisk™ Genes: MLH1, MSH2, MSH6, PMS2, EPCAM, TP53, PTEN, STK11


2. Lucenteforte E, Talamini R, Montella M, Dal Maso L, Pelucchi C, Fran-ceschi S, La Vecchia C, Negri E. Family history of cancer and the risk of endometrial cancer. Eur J Cancer Prev. 2009 Apr;18(2):95-9. doi: 10.1097/CEJ.0b013e328305a0c9. PubMed PMID: 19337055.

3. Gruber SB, Thompson WD. A population-based study of endometrial cancer and familial risk in younger women. Cancer and Steroid Hormone Study Group. Cancer Epidemiol Biomarkers Prev. 1996 Jun;5(6):411-7. PubMed PMID: 8781735.

4. American Society of Clinical Oncology: Uterine Cancer (http://www.cancer.net/cancer-types/uterine-cancer) Dec 10, 2013.

5. American Cancer Society: Endometrial Cancer (http://www.cancer.org/cancer/endometrialcancer/index) Dec 10, 2013.

6. National Cancer Institute: Endometrial Cancer treatment (http://www.cancer.gov/cancertopics/pdq/treatment/endometrial/patient) Dec 10, 2013.

Stage II Endometrial Cancer



Syndrome & Gene Overview



Hereditary Breast & Ovarian Cancer Syndrome (HBOC)

Syndrome Name Gene Cancer Site

Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

BRCA1 BREAST OVARIAN -- PANCREATIC PROSTATE

BRCA2 BREAST OVARIAN MELANOMA PANCREATIC PROSTATE

Hereditary Breast and Ovarian Cancer syndrome (HBOC) The genetic basis of Hereditary Breast and Ovarian Cancer

syndrome (HBOC) is an inherited mutation in either the

BRCA1 or BRCA2 genes. Normally, the proteins produced

by the BRCA1 and BRCA2 genes prevent cells from becom-

ing malignant by aiding in the repair of mutations in other

genes through a process known as double-stranded DNA

repair. Therefore, an inherited mutation in either of these

genes greatly increases the probability of a cell becoming

cancerous. It is believed that approximately 7% of breast

cancer cases and 11% to 15% of ovarian cancer cases are

caused by inherited mutations in BRCA1 or BRCA2.

Women with HBOC due to mutations in BRCA1 or BRCA2

have a greatly increased risk for both breast and ovarian

cancer. Men with HBOC have an increased risk for male

breast cancer and prostate cancer. Both men and women

with HBOC may also have an increased risk for pancreatic

cancer and melanoma. These cancers are often diagnosed

at younger ages than are usually seen in the general pop-

ulation.

A small proportion of apparent cases of HBOC may be

due to inherited mutations in genes other than BRCA1 and BRCA2. Some candidate genes, such as RAD51C and

BRIP1, have already been identified and are included as

part of the Myriad myRisk™ test. There is good evidence

that mutations in these genes increase the risk of breast

and ovarian cancer, but the risks do not seem to be as high

as with mutations in BRCA1 and BRCA2.

Myriad myRisk includes comprehensive analysis of both

BRCA1 and BRCA2, as well as other genes known to have a

role in the risk for breast and/or ovarian cancer.

Although there are high risks for cancer in patients with

HBOC, many of these risks can be greatly reduced with

appropriate medical management. Guidelines for the med-

ical management of patients with HBOC syndrome have

been developed by the National Comprehensive Cancer

Network (NCCN), and other expert groups.

Although mutations in both BRCA1 and BRCA2 cause

HBOC, the exact cancer risks and medical management

guidelines differ between the genes.

Please use the information in the subsequent pages for

a summary of the associated gene mutation. This clinical

information can be found as part of the Myriad myRisk

report for a patient found to have a mutation in that gene.

This includes information about specific cancer risks and

an overview of medical management guidelines.



BRCA1 - Gene Risk Summary / Overview

Gene Syndrome Cancer Site

BRCA1 Hereditary Breast and Ovarian Cancer Syndrome (HBOC) BREAST OVARIAN PANCREATIC PROSTATE

BRCA1 Gene Overview

Hereditary Breast and Ovarian Cancer syndrome (HBOC)1

• Individuals with mutations in BRCA1 have a condition

called Hereditary Breast and Ovarian Cancer syndrome

(HBOC).

• Women with HBOC have a high risk for developing breast

and ovarian cancer. There are also high risks for fallopian

tube cancer and primary peritoneal cancer.

• Men with HBOC due to mutations in BRCA1 have an ele-

vated risk for breast and prostate cancer. The increased

risk for prostate cancer may be most significant at

younger ages.

BRCA1 Gene Cancer Risk Table

CANCER AGE RANGECANCER

RISKRISK FOR GENERAL

POPULATION2

Female Breast

To age 50 Up to 51%7 1.9%

To age 70 Up to 87%8 7.3%

Second primary within 5 years of a first diagnosis Up to 20%9 2%

Ovarian

To age 50 Up to 23%7 0.2%

To age 70 Up to 44%8 0.7%

Ovarian cancer within 10 years of a breast cancer diagnosis Up to 12.7%10 <1%

Pancreatic To age 80 Elevated risk4 1%

Prostate To age 70 Up to 16%5,6 8.2%

Male Breast To age 70 Up to 1.2%3 <0.1%

High Risk Elevated Risk

• Male and female patients with HBOC due to mutations in

BRCA1 have an elevated risk for pancreatic cancer.

• Although there are high cancer risks for patients with

HBOC, there are interventions that have been shown to be

effective at reducing many of these risks. Guidelines from

the National Comprehensive Cancer Network (NCCN)

for the medical management of patients with HBOC are

listed on the following page. It is recommended that

patients with BRCA1 mutations and a diagnosis of HBOC

be managed by a multidisciplinary team with experience

in the prevention and treatment of the cancers associ-

ated with HBOC.




BRCA1 Gene Cancer Risk Management Table

CANCER PROCEDURE AGE TO BEGIN FREQUENCY

FemaleBreast

Breast awareness—Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness1

18 years NA

Consider options for breast cancer chemoprevention (i.e., Tamoxifen)1 Individualized NA

Clinical breast exam1 25 years Every 6 to 12 months

Mammography and breast MRI125 years, or individualized to a younger age based on the earliest diagnosis in family

Annually

Consider risk-reducing mastectomy1 Individualized NA

Ovarian

Consider options for ovarian cancer chemoprevention (i.e., oral contraceptives)1 Individualized NA


35 to 40 years, after completion of childbearing, or individualized to a younger age based on the earliest diagnosis in the family

NA


30 years, or individualized to a younger age based on the earliest diagnosis in the family

Every 6 months

PancreaticCurrently there are no specific medical management guidelines for pancreatic cancer risk1 NA NA

Prostate

Start risk and benefit discussion about offering baseline digital rectal examination (DRE) and Prostate Specific Antigen (PSA), incorporating information about increased prostate cancer risk1

40 years Annually

Male Breast

Breast self-exam1 35 years Monthly


Consider mammography1 40 years Individualized

REFERENCES: 1. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 2. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 3. Tai YC, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007 99:1811-4. PMID: 18042939. 4. Lynch HT, et al. BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. Cancer Genet Cytogenet. 2005 158:119-25. PMID: 15796958. 5. Struewing JP, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997 336:1401-8. PMID: 9145676. 6. Liede A, et al. Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol. 2004 22:735-42. PMID: 14966099. 7. Easton DF, et al. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 56:265-71. PMID: 7825587, 8. Ford D, et al. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994 343:692-5. PMID: 7907678. 9. Verhoog LC, et al. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet. 1998 351:316-21. PMID: 9652611. 10. Met-calfe KA, et al. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol. 2005 96:222-6. PMID: 15589605.






BRCA2 Hereditary Breast and Ovarian Cancer Syndrome (HBOC) BREAST OVARIAN MELANOMA PANCREATIC PROSTATE

BRCA2 Gene Overview

Hereditary Breast and Ovarian Cancer syndrome (HBOC)1

• Individuals with mutations in BRCA2 have a condition

called Hereditary Breast and Ovarian Cancer syndrome

(HBOC).

• Women with HBOC have a high risk for developing breast

and ovarian cancer. There are also high risks for fallopian

tube cancer and primary peritoneal cancer.

• Men with HBOC due to mutations in BRCA2 have a high

risk for breast cancer and an elevated risk for prostate

cancer. The increase in prostate cancer risk is most sig-

nificant at younger ages.

BRCA2 Gene Cancer Risk Table

CANCER AGE RANGE CANCER RISKRISK FOR GENERAL

POPULATION2

Female Breast

To age 50 Up to 28%5 1.9%

To age 70 Up to 84%5 7.3%

Second primary within 5 years of a first diagnosis

12%6 2%

Ovarian

To age 70 Up to 27%5 0.7%

Ovarian cancer within 10 years of a breast cancer diagnosis

6.8%7 <1.0%

Pancreatic To age 807%, or higher if there is a family his-tory of pancreatic cancer 8,9 1%

Male Breast To age 70 6.8%4 <0.1%

Prostate To age 70 20%4 8.2%

Melanoma To age 80 Elevated risk3 1.6%


• Male and female patients with HBOC due to a mutation

in BRCA2 also have a high risk for pancreatic cancer and

an elevated risk for melanoma.

• Although there are high cancer risks for patients with

HBOC, there are interventions that have been shown to be

effective at reducing many of these risks. Guidelines from

the National Comprehensive Cancer Network (NCCN)

for the medical management of patients with HBOC are

listed on the following page. It is recommended that

patients with BRCA2 mutations and a diagnosis of HBOC


in the prevention and treatment of the cancers associ-

ated with HBOC.




BRCA2 Gene Cancer Risk Management Table


Female Breast

Breast awareness—Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness1

18 years NA

Consider options for breast cancer chemoprevention (i.e., Tamoxifen)1 Individualized NA


Mammography and breast MRI125 years, or individualized to a younger age based on the earliest diagnosis in family

Annually


Ovarian

Consider options for ovarian cancer chemoprevention (i.e., oral contraceptives)1 Individualized NA


35 to 40 years, after comple-tion of childbearing, or individ-ualized to a younger age based on the earliest diagnosis in the family

NA


30 years, or individualized to a younger age based on the earliest diagnosis in the family

Every 6 months

Pancreatic

Consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic reso-nance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a mul-tidisciplinary team with experience in the screening for pancreatic cancer, preferably within research protocols9

Individualized NA

Male Breast

Breast self-exam1 35 years Monthly


Consider mammography1 40 years Individualized

Prostate


40 years Annually

Melanoma Consider whole body skin exams1 Individualized NA

REFERENCES: 1. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 2. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 3. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999 91:1310-6. PMID: 10433620. 4. Tai YC, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007 99:1811-4. PMID: 18042939. 5. Ford D, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998 62:676-89. PMID: 9497246. 6. Verhoog LC, et al. Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol. 1999 17:3396-402. PMID: 10550133. 7. Metcalfe KA, et al. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol. 2005 96:222-6. PMID: 15589605. 8. van Asperen CJ, et al. Netherlands Collaborative Group on Hereditary Breast Cancer (HEBON) . Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet. 2005 42:711-9. PMID: 16141007. 9. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763. 10. Alter BP, Kupfer G. Fanconi Anemia. In: Pagon RA, et al., editors. GeneReviews. 2013 Available from http://www.ncbi.nlm.nih.gov/books/NBK1401/. PMID: 20301575.




Lynch Syndrome

Syndrome Gene Cancer Site

Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

MLH1

OVARIAN COLORECTAL ENDOMETRIAL PANCREATIC GASTRIC

OTHER CANCERS /CLINICAL FEATURES

MSH2

MSH6

PMS2

EPCAM

Lynch Syndrome / Hereditary Non- Polyposis Colorectal Cancer (HNPCC)

Lynch syndrome, also known as Hereditary Non-Polyp-

osis Colorectal Cancer (HNPCC), is the most common of

the hereditary colon cancer syndromes and is believed

to account for 3% to 5% of all colorectal cancers. Henry

T. Lynch, M.D., described the features of this syndrome in

1966 while conducting familial colorectal cancer studies. A

variety of names followed, but the term Lynch syndrome

was first used in 1984 to help clarify the disease and to

honor Dr. Lynch’s work.

It is now known that Lynch syndrome results from an

inherited mutation in one of the mismatch repair (MMR)

genes. Normally, MMR genes produce proteins that iden-

tify and correct base-pairing mismatches that can occur

during DNA replication. Consequently, a mutation that

inactivates an MMR gene leads to accumulation of other

mutations which significantly increases the likelihood of

developing cancer. Mutations in any one of five genes can

disrupt the mismatch repair function of cells and cause

Lynch syndrome (MLH1, MSH2, MSH6, EPCAM and PMS2).

Myriad myRisk™ includes comprehensive testing of all five

of these genes.

The most significant cancer risks for patients with Lynch

syndrome are colorectal and endometrial cancer, but there

are also increased risks for many other cancers, including

ovarian, gastric, small bowel, ureter/renal pelvis, hepatobi-

liary tract, brain (usually glioblastoma), sebaceous gland,

and pancreatic.

Although there are high risks for cancer in patients with

Lynch syndrome, many of these risks can be greatly

reduced with appropriate medical management. Guide-

lines for the medical management of patients with Lynch

syndrome have been developed by the National Compre-

hensive Cancer Network (www.nccn.org) and other expert

groups.

Although mutations in any of the five genes listed above

can cause Lynch syndrome, the exact cancer risks and

medical management guidelines differ between the genes.









MLH1 - Gene Risk Summary / Overview


MLH1Lynch Syndrome / Hereditary Non- Polyposis Colorectal Cancer (HNPCC)


OTHER CANCERS

/ CLINICAL FEATURES

MLH1 Gene Overview

Lynch syndrome1,2,3,4,5,6

• Individuals with mutations in MLH1 have a condition

called Lynch syndrome. This condition is also known as

Hereditary Non-Polyposis Colon Cancer (HNPCC).

• Men and women with Lynch syndrome due to mutations

in MLH1 have a high risk of developing colorectal can-

cer, often at young ages. Colorectal cancer in patients

with Lynch syndrome develops from adenomatous pol-

yps which progress to cancer more quickly than polyps

in individuals who do not have Lynch syndrome.

• Women with Lynch syndrome due to mutations in MLH1 have a high risk for developing endometrial and ovarian

cancer, often at young ages.

• Patients with Lynch syndrome due to mutations in MLH1 also have an increased risk of developing a wide variety

of other cancers, including gastric, small bowel, ureter/

renal pelvis, hepatobiliary tract, brain (usually glioblas-

toma), sebaceous gland, and pancreatic.

• Patients with Lynch syndrome have a high risk for

MLH1 Gene Cancer Risk Table

CANCER AGE RANGE CANCER RISK RISK FOR GENERAL POPULATION 7

Colorectal To age 70 52%-82%1,2 1.9%

Endometrial To age 70 25%-60%1,2 1.6%

Gastric To age 70 6%-13%1,2 0.3%

Ovarian To age 70 4%-12%1,2 0.7%

Sebaceous Neoplasms To age 70 1%-9%1,2 <1.0%

Small Bowel To age 70 3%-6%1,2 0.1%

Ureter/Renal Pelvis To age 70 1%-4%1,2 <1.0%

Hepatobiliary Tract To age 70 1.4%-4%1,2 0.4%

Pancreatic To age 70 1%-6%1,2,3 0.5%

Central Nervous System To age 70 1%-3%1,2 0.4%


developing second primary cancers following an ini-

tial diagnosis of colorectal or endometrial cancer. This

includes a high risk for endometrial cancer in women fol-

lowing colorectal cancer and vice versa, a high risk for a

second primary colorectal cancer in any portions of the

colon or rectum remaining after surgical treatment and

a high risk for other Lynch associated cancers, such as

those of the upper gastrointestinal tract, ureter/renal pel-

vis, and other sites.

• Although there are high risks for cancer in patients with





hensive Cancer Network (NCCN) and other expert groups.

It is recommended that patients with an MLH1 mutation

and a diagnosis of Lynch syndrome be managed by a

multidisciplinary team with expertise in medical genetics

and the care of patients with this condition.



MLH1 - Gene Risk Summary / Overview

MLH1 Gene Cancer Risk Management Table


Colorectal Colonoscopy1

20 to 25 years, or individualized to a younger age based on the earliest diagnosis in family

Every 1 to 2 years

Endometrial

Patient education about endometrial cancer symptoms1 Individualized NA

Consider endometrial sampling1 Individualized Annually

Consider hysterectomy1 After completion of childbearing

NA

GastricConsider upper endoscopy, particularly for patients with additional risk factors for gastric cancer, such as family history or Asian ancestry1

30 to 35 years Every 3 to 5 years

Ovarian

Consider bilateral salpingo-oophorectomy1 After completion of childbearing

NA

Consider transvaginal ultrasound and CA-125 measurement1 Individualized NA

Sebaceous Neoplasms

Currently there are no specific medical management guidelines for sebaceous neoplasm risk

NA NA

Small BowelConsider upper endoscopy, particularly for patients with additional risk factors for small bowel cancer, such as family history1


Ureter/Renal Pelvis

Consider urinalysis1 25 to 30 years Annually

Hepatobiliary Tract

Currently there are no specific medical management guidelines for hepatobiliary cancer risk in mutation carriers

NA NA

Pancreatic

Consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in the screen-ing for pancreatic cancer, preferably within research protocols.8

Individualized NA

Central Nervous System

Physical exam1 25 to 30 years Annually

REFERENCES: 1. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 2. Kohlmann W, Gruber SB. Lynch syndrome. In: Pagon RA, et al., editors. GeneReviews. 2012 Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/. PMID: 20301390. 3. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671. 4. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626. 5. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444. 6. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731. 7. Surveillance Research Program, National Cancer Institute SEER*Stat soft-ware (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 8. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763.




MSH2 - Gene Risk Summary / Overview


MSH2Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer (HNPCC)


OTHER CANCERS

/ CLINICAL FEATURES

MSH2 Gene OverviewLynch syndrome1,2,3,4,5,6

• Individuals with mutations in MSH2 have a condition




in MSH2 have a high risk of developing colorectal cancer,

often at young ages. Colorectal cancer in patients with

Lynch syndrome develops from adenomatous polyps

which progress to cancer more quickly than polyps in

individuals who do not have Lynch syndrome.

• Women with Lynch syndrome due to mutations in MSH2

have a high risk for developing endometrial and ovarian


• Patients with Lynch syndrome due to mutations in MSH2

also have an increased risk of developing a wide variety

of other cancers, including gastric, small bowel, ureter/

renal pelvis, hepatobiliary tract, brain (usually glioblas-

toma), sebaceous gland, and pancreatic.

MSH2 Gene Cancer Risk Table




Gastric To age 70 6%-13%1,2 0.3%

Ovarian To age 70 4%-12%1,2 0.7%








• Patients with Lynch syndrome have a high risk for

developing second primary cancers following an ini-

tial diagnosis of colorectal or endometrial cancer. This

includes a high risk for endometrial cancer in women

following colorectal cancer and vice versa, a high risk

for a second primary colorectal cancer in any portions of

the colon or rectum remaining after surgical treatment

and a high risk for other Lynch associated cancers, such

as those of the upper gastrointestinal tract, ureter/renal

pelvis, and other sites.






hensive Cancer Network (NCCN) and other expert groups.

It is recommended that patients with an MSH2 mutation

and a diagnosis of Lynch syndrome be managed by a

multidisciplinary team with expertise in medical genetics

and the care of patients with this condition.




MSH2 Gene Cancer Risk Management Table




Every 1 to 2 years

Endometrial




NA

GastricConsider upper endoscopy and/or capsule endoscopy1 30 to 35 years Every 3 to 5 years

Ovarian


NA




Sebaceous Neoplasms

Currently there are no specific medical management guidelines for sebaceous neoplasm risk in mutation carriers

NA NA

Pancreatic

Consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in the screening for pancreatic cancer, preferably within research protocols.8

Individualized NA

Hepatobiliary Tract


NA NA

Ureter/Renal Pelvis




REFERENCES: 1. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 2. Kohlmann W, Gruber SB. Lynch syndrome. In: Pagon RA, et al., editors. GeneReviews. 2012 Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/. PMID: 20301390. 3. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671. 4. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626. 5. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444. 6. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731. 7. Surveillance Research Program, National Cancer Institute SEER*Stat soft-ware (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 8. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763.






MSH6Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

OVARIAN COLORECTAL ENDOMETRIAL PANCREATIC GASTRICOTHER CANCERS

/ CLINICAL FEATURES

MSH6 Gene Overview


• Individuals with mutations in MSH6 have a condition




in MSH6 have a high risk of developing colorectal cancer,

often at younger ages than seen in the general popula-

tion. Colorectal cancer in patients with Lynch syndrome

develops from adenomatous polyps which progress to

cancer more quickly than polyps in individuals who do

not have Lynch syndrome. Colorectal cancer risk may be

somewhat lower in women than in men, but there are no

differences in the colorectal cancer screening guidelines

for men and women.

• Women with Lynch syndrome due to mutations in MSH6

have a high risk for developing endometrial cancer and

an elevated risk for ovarian cancer, often at younger ages

than typical in the general population.

• Patients with Lynch syndrome due to mutations in MSH6

are also believed to have an increased risk of develop-

ing a wide variety of other Lynch syndrome associated

cancers, including gastric, small bowel, ureter/renal

pelvis, hepatobiliary tract, brain (usually glioblastoma),

sebaceous gland, and pancreatic. Precise risk estimates

MSH6 Gene Cancer Risk Table


Male Colorectal To age 70 22%-69%5,6,7 2.2%

Female Colorectal To age 70 10%-30%5,6,7 1.7%

Endometrial To age 70 16%-71%5,6,7 1.6%

Sebaceous Neoplasms To age 70 Elevated risk1,2,5,6,7 <1.0%

Ovarian To age 70 Elevated risk1,2,5,6,7 0.7%

Small Bowel To age 70 Elevated risk1,2,5,6,7 0.1%

Gastric To age 70 Elevated risk1,2,5,6,7 0.3%

Ureter/Renal Pelvis To age 70 Elevated risk1,2,5,6,7 <1.0%

Hepatobiliary Tract To age 70 Elevated risk1,2,5,6,7 0.4%

Pancreatic To age 70 Elevated risk1,10,11 0.5%

Central Nervous System To age 70 Elevated risk1,2,5,6,7 0.4%


are not available, because there is less information avail-

able for patients with MSH6 mutations compared with

patients who have mutations in other Lynch syndrome

genes.

• Patients with Lynch syndrome have a high risk for devel-

oping second primary cancers following an initial diag-

nosis of colorectal or endometrial cancer. This includes

a high risk for endometrial cancer in women following

colorectal cancer and vice versa, a high risk for a second

primary colorectal cancer in any portions of the colon

or rectum remaining after surgical treatment and an

increased risk for other Lynch associated cancers, such

as those of the upper gastrointestinal tract, ureter/renal

pelvis, and other sites.





syndrome have been developed by the National Com-

prehensive Cancer Network (NCCN) and other expert

groups. It is recommended that patients with an MSH6

mutation and a diagnosis of Lynch syndrome be man-

aged by a multidisciplinary team with expertise in medi-

cal genetics and the care of patients with this condition.




MSH6 Gene Cancer Risk Management Table




Every 1 to 3 years depending on patient age

Endometrial



NA

Sebaceous Neoplasms


NA NA

Ovarian Consider bilateral salpingo-oophorectomy1 After completion of childbearing

NA

Small BowelCurrently there are no specific medical management guidelines for small bowel cancer risk in mutation carriers

NA NA

GastricCurrently there are no specific medical management guidelines for gastric cancer risk in mutation carriers

NA NA

Ureter/Renal Pelvis

Currently there are no specific medical management guidelines for ureter/renal pelvis cancer risk in muta-tion carriers

NA NA

Hepatobiliary Tract


NA NA

Pancreatic

Consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic reso-nance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a mul-tidisciplinary team with experience in the screening for pancreatic cancer, preferably within research protocols.10

Individualized NA

Central Ner-vous System

Currently there are no specific medical management guidelines for central nervous system cancer risk in mutation carriers

NA NA

REFERENCES: 1. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 2. Kohlmann W, Gruber SB. Lynch syndrome. In: Pagon RA, et al., editors. GeneReviews. 2012 Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/. PMID: 20301390. 3. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626. 4. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444. 5. Hendriks YM, et al. Cancer risk in hereditary nonpolyposis colorectal cancer due to MSH6 mutations: impact on counseling and surveillance. Gastroenterology. 2004 127:17-25. PMID: 15236168. 6. Bonadona V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA. 2011 305:2304-10. PMID: 21642682. 7. Baglietto L, et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010 102:193-201. PMID: 20028993. 8. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731. 9. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 10. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763. 11. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671.




PMS2 - Gene Risk Summary / Overview


PMS2Lynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer (HNPCC)


/ CLINICAL FEATURES

PMS2 Gene Overview


• Individuals with mutations in PMS2 have a condition




in PMS2 have a high risk of developing colorectal cancer,

often at younger ages than seen in the general popula-

tion. Colorectal cancer in patients with Lynch syndrome

develops from adenomatous polyps which progress to

cancer more quickly than polyps in individuals who do

not have Lynch syndrome.

• Women with Lynch syndrome due to mutations in PMS2

have a high risk for developing endometrial cancer and

an elevated risk for ovarian cancer, often at younger ages

than typical in the general population.

• Patients with Lynch syndrome due to mutations in PMS2

are also believed to have an increased risk of developing

a wide variety of other Lynch syndrome associated can-

cers, including gastric, small bowel, ureter/renal pelvis,

hepatobiliary tract, brain (usually glioblastoma), seba-

ceous gland, and pancreatic. Precise risk estimates are

PMS2 Gene Cancer Risk Table


Colorectal To age 70 Up to 20%3 1.9%

Endometrial To age 70 Up to 15%3 1.6%

Sebaceous Neoplasms To age 70 Elevated risk1,2,3 <1.0%

Ovarian To age 70 Elevated risk1,2,3 0.7%

Small Bowel To age 70 Elevated risk1,2,3 0.1%

Gastric To age 70 Elevated risk1,2,3 0.3%

Ureter/Renal Pelvis To age 70 Elevated risk1,2,3 <1.0%

Hepatobiliary Tract To age 70 Elevated risk1,2,3 0.4%

Pancreatic To age 70 Elevated risk1,2,3,4,9 0.5%

Central Nervous System To age 70 Elevated risk1,2,3 0.4%


not available, because there is less information available

for patients with PMS2 mutations compared with patients

who have mutations in other Lynch syndrome genes.







or rectum remaining after surgical treatment and a high

risk for other Lynch associated cancers, such as those of

the upper gastrointestinal tract, ureter/renal pelvis, and

other sites.





syndrome have been developed by the National Com-

prehensive Cancer Network (NCCN) and other expert

groups. It is recommended that patients with an PMS2

mutation and a diagnosis of Lynch syndrome be man-

aged by a multidisciplinary team with expertise in medi-

cal genetics and the care of patients with this condition.



PMS2 - Gene Risk Summary / Overview

PMS2 Gene Cancer Risk Management Table



35 to 40 years, or individual-ized to a younger age based on the earliest diagnosis in family

Every 1 to 3 years depending on patient age

EndometrialPatient education about endometrial cancer symptoms1 Individualized NA

Sebaceous Neoplasms


NA NA

OvarianCurrently there are no specific medical management guidelines for ovarian cancer risk in mutation carriers

NA NA


NA NA

GastricCurrently there are no specific medical management guidelines for gastric cancer risk in mutation carriers

NA NA

Ureter/Renal Pelvis

Currently there are no specific medical management guidelines for ureter/renal pelvis cancer risk in muta-tion carriers

NA NA

Hepatobiliary Tract


NA NA

Pancreatic

Consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic reso-nance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a mul-tidisciplinary team with experience in the screening for pancreatic cancer, preferably within research protocols.9

Individualized NA


Currently there are no specific medical management guidelines for central nervous system cancer risk in mutation carriers

NA NA

REFERENCES: 1. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 2. Kohlmann W, Gruber SB. Lynch syndrome. In: Pagon RA, et al., editors. GeneReviews. 2012 Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/. PMID: 20301390. 3. Senter L, et al. The clinical phenotype of Lynch syndrome due to germline PMS2 mutations. Gastroenterology. 2008 135419-28. PMID: 18602922. 4. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671. 5. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626. 6. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444. 7. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731. 8. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 9. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763.




EPCAM - Gene Risk Summary / Overview


EPCAMLynch Syndrome / Hereditary Non-Polyposis Colorectal Cancer (HNPCC)


/ CLINICAL FEATURES

EPCAM Gene Overview

Lynch syndrome1,2,3,4,5,6,7

• Individuals with mutations in EPCAM have a condition




in EPCAM have a high risk of developing colorectal can-

cer, often at young ages. Colorectal cancer in patients

with Lynch syndrome develops from adenomatous pol-

yps which progress to cancer more quickly than polyps

in individuals who do not have Lynch syndrome.

• Women with Lynch syndrome due to mutations in EPCAM

have a high risk for developing endometrial and ovarian


• Patients with Lynch syndrome due to mutations in EPCAM

are also believed to have an increased risk of developing

a wide variety of other cancers, including gastric, small

bowel, ureter/renal pelvis, hepatobiliary tract, brain (usu-

ally glioblastoma), sebaceous gland, and pancreatic.







or rectum remaining after surgical treatment, and a high

risk for other Lynch associated cancers, such as those of

the upper gastrointestinal tract, ureter/renal pelvis, and

other sites.

• Cancer risks for patients with Lynch syndrome due to

mutations in EPCAM are currently estimated to be similar

to those for patients with Lynch syndrome due to muta-

tions in MSH2 and medical management guidelines are

currently the same for patients with mutations in either

gene. However, it is possible that this will change over

time as we learn more about the exact risks associated

with mutations in EPCAM. There are some early indica-

tions that endometrial cancer risk may be much lower for

women with certain types of mutations in EPCAM.

• Although there are high risks for cancer in patients

with Lynch syndrome, many of these risks can be

greatly reduced with appropriate medical management.

Guidelines for the medical management of patients with

Lynch syndrome have been developed by the National

Comprehensive Cancer Network (NCCN) and other

expert groups. It is recommended that patients with an

EPCAM mutation and a diagnosis of Lynch syndrome

be managed by a multidisciplinary team with expertise

in medical genetics and the care of patients with this

condition.

High Risk Elevated RiskEPCAM Gene Cancer Risk Table




Gastric To age 70 6%-13%1,2 0.3%

Ovarian To age 70 4%-12%1,2 0.7%









EPCAM - Gene Risk Summary / Overview

REFERENCES: 1. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 2. Kohlmann W, Gruber SB. Lynch syndrome. In: Pagon RA, et al., editors. GeneReviews. 2012 Available from http://www.ncbi.nlm.nih.gov/books/NBK1211/. PMID: 20301390. 3. Kastrinos F, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA. 2009 302:1790-5. PMID: 19861671. 4. Lin KM, et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum. 1998 41:428-33. PMID: 9559626. 5. Win AK, et al. Risks of colorectal and other cancers after endometrial cancer for women with Lynch syndrome. J Natl Cancer Inst. 2013 105:274-9. PMID: 23385444. 6. Win AK, et al. Risks of primary extracolonic cancers following colorectal cancer in lynch syndrome. J Natl Cancer Inst. 2012 104:1363-72. PMID: 22933731. 7. Kempers MJ, et al. Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study. Lancet. Oncol. 2011 12:49-55. PMID: 21145788. 8. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 9. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763.

EPCAM Gene Cancer Risk Management Table




Every 1 to 2 years

Endometrial




NA

GastricConsider upper endoscopy, particularly for patients with additional risk factors for gastric cancer, such as family history or Asian ancestry1


Ovarian


NA




Sebaceous Neoplasms


NA NA

Pancreatic


Individualized NA

Hepatobiliary Tract

Currently there are no specific medical management guidelines for hepatobiliary cancer risk

NA NA

Ureter/Renal Pelvis








Familial Adenomatous Polyposis (FAP)/ Attenuated FAP (AFAP)

APC COLORECTAL PANCREATIC GASTRICOTHER CANCERS /

CLINICAL FEATURES


Familial Adenomatous Polyposis (FAP)/Attenuated FAP

(AFAP) is a hereditary colorectal cancer condition in

which patients develop multiple adenomatous polyps in

the colon and/or rectum, leading to a high risk for cancer.

The distinction between FAP and AFAP is largely based on

the numbers of polyps present – patients with < 100 pol-

yps are said to have AFAP, and those with higher numbers,

which can range up into the thousands, are said to have

FAP. These polyps may be present at young ages, even in

children.

The majority of patients with a diagnosis of FAP have

mutations in the APC gene. There are indications that

the location and type of mutation influences whether the

patient has FAP or AFAP, and may also influence the risks

for other cancer and non-cancer features of the condition.

Some apparent cases of FAP/AFAP are caused by muta-

tions in the MUTYH gene. Patients with MUTYH mutations

are more likely to have polyp counts similar to those seen

in patients with AFAP. Patients with MUTYH mutations

have the condition, MUTYH-associated Polyposis (MAP).

MUTYH gene testing is also included as part of Myriad

myRisk™.

In the past, FAP/AFAP has been known as Turcot syndrome

when seen with central nervous system tumors, and Gard-

ner syndrome when seen with osteomas and soft tissue

tumors. These names are used rarely now that it is rec-

ognized that mutations in the APC gene are the common

underlying cause of both conditions.

The numerous colorectal polyps in the colon and rectum of

patients with FAP/AFAP can give rise to cancers, leading

to a high risk for colorectal cancer. Additional risks include

cancers of the thyroid, small bowel, pancreas, hepatoblas-

toma (during early childhood) and central nervous system

(in particular, medulloblastoma).

Patients with FAP, and to a lesser extent, patients with

AFAP, are at risk for extracolonic manifestations, including

desmoid tumors, osteomas, epidermoid cysts, supernu-

merary teeth, and pigmented spots on the retina known as

Congenital Hypertrophy of the Retinal Pigment Epithelium

(CHRPE).

Although there are high risks for cancer and other clinical

problems for patients with FAP/AFAP, many of these risks

can be greatly reduced with appropriate medical man-

agement. Guidelines for the management of patients with

FAP/AFAP have been developed by the National Compre-

hensive Cancer Network (NCCN) (www.nccn.org).



information can be found as part of the Myriad myRisk™







APC - Gene Risk Summary / Overview


APCFamilial Adenomatous Polyposis (FAP)/ Attenuated FAP (AFAP)

COLORECTAL PANCREATIC GASTRICOTHER CANCERS

/ CLINICAL FEATURES

APC Gene OverviewFamilial Adenomatous Polyposis (FAP)/Attenuated Familial Adenomatous Polyposis (AFAP)1,2,5,6

• Individuals with APC mutations have either Familial Adenomatous Polyposis syndrome (FAP) or Attenuated Familial Adenomatous Polyposis syndrome (AFAP). The distinction between FAP and AFAP is based on the number of adenomatous polyps found in the patient, as described below.

• Patients with FAP/AFAP have a greatly increased risk for colorectal cancer, often at very young ages.

• Patients with FAP/AFAP are likely to develop large num-bers of adenomatous polyps in the GI system, particularly in the colon, rectum, stomach and small bowel. Patients with 100 or more polyps are said to have a diagnosis of FAP and patients with less than 100 polyps are said to have a diagnosis of AFAP. These polyps begin to form at an average age of 16, but can be found in individuals as young as age 7.

• Patients with FAP/AFAP also have an elevated risk for other cancers, most notably cancer of the small bowel. There are also smaller risks for childhood hepatoblas-toma, and cancers of the thyroid, pancreas, and central nervous system (CNS).

• Gastric polyps are common, but the risk for gastric can-cer is not thought to be significantly increased in patients living in Western cultures. A more significantly increased risk for gastric cancer has been observed in Japanese and Korean patients.

APC Gene Cancer Risk Table



Colorectal

AFAP to age 80 >70%1,2 3.4%

FAP to age 21 7%1,2 <0.01%

FAP to age 50 93%1,2 0.3%

FAP to age 80 >99%1,2 3.4%

Other - Desmoid Tumors To age 80 10%-30%2 <0.04%

Gastric To age 80Slightly increased in Western cultures, but may be significantly increased in cultures with a higher baseline gastric cancer rate1,2

0.6%

Thyroid To age 80 1%-2%1,2 1%

Pancreatic To age 80 Possibly elevated1,2 1%

Hepatoblastoma To age 5 1%-2%1,2 <0.001%

Central Nervous System To age 80 1%1,2 0.5%

• Patients with FAP, and less commonly, patients with AFAP, can have clinical findings other than cancer, such as osteomas, dental abnormalities, congenital hyper-trophy of the retinal pigment epithelium (CHRPE) and benign cutaneous lesions. Desmoid tumors, which occur in some individuals with FAP, are the most serious cause of morbidity among affected individuals outside of can-cer, and may be triggered by abdominal surgery.

• Although there are high risks for cancer in patients with FAP/AFAP, these risks can be greatly reduced with appropriate medical management. Guidelines from the National Comprehensive Cancer Network (NCCN) are listed in the following tables. It is recommended that patients with APC mutations and a diagnosis of FAP or AFAP be managed by a multidisciplinary team with experience in the prevention and treatment of the com-plications associated with hereditary colorectal cancer conditions.

APC I1307K Clinical Considerations• The APC I1307K variant is common in the Ashkenazi Jew-

ish population, where it is found in up to 10.1% of individ-uals. This variant does not cause Familial Adenomatous Polyposis (FAP) syndrome, which is normally associated with other clinically significant variants in the APC gene.

• Ashkenazi Jewish individuals with this finding have an elevated risk for developing colon polyps and colon cancer compared to colon cancer risk for general pop-ulation. The exact degree of this increase in risk has not been established, but is believe to be relatively small. APC I1307K has also been found in patients of ancestries other than Ashkenazi Jewish, but has not been shown to increase cancer risks in these individuals.




APC - Gene Risk Summary / Overview

APC Gene Cancer Risk Management Table


Small BowelUpper endoscopy with side-viewing endoscope, consider MRI or CT visualization1 25 to 30 years Every 4 years

Colorectal

Consider chemoprevention with NSAIDs to reduce adenoma burden after surgery1 NA NA

Colorectal surgical evaluation and counseling1

Based on cancer diagnosis and/or adenoma number, size and histology

NA

Sigmoidoscopy or colonoscopy1 10 to 15 years Annually

Desmoid Tumor

Abdominal palpation with consideration of abdominal MRI or CT1

1 to 3 years post-colectomy

Every 5 to 10 years, or with symptoms

Gastric Upper endoscopy1 25 to 30 years Every 4 years

Thyroid Thyroid exam and/or consider ultrasound1 Late teens Annually

PancreaticCurrently there are no specific medical management guidelines for pancreatic cancer risk in mutation carriers

NA NA

HepatoblastomaConsider liver palpation, abdominal ultrasound, and alpha-fetoprotein (AFP) measurement1 Infancy

Every 3 to 6 months during first 5 years of life


Physical exam1 Late teens Annually

REFERENCES: 1. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 2. Jasperson KW, Burt RW. APC-Associated Polyposis Conditions. In: Pagon RA, et al., editors. GeneReviews. 2011 Available from: http://www.ncbi.nlm.nih.gov/books/NBK1345/. PMID: 20301519. 3. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 4. Aretz S, et al. Somatic APC mosaicism: a frequent cause of familial adenomatous polyposis (FAP). Hum Mutat. 2007 28:985-92. PMID: 20301443. 5. Boursi B, et al. The APC p.I1307K polymorphism is a significant risk factor for CRC in average risk Ashkenazi Jews. Eur J Cancer. 2013 49:3680-5. PubMed PMID: 23896379. 6. Liang J, et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am J Epidemiol. 2013 177:1169-79. PMID:23576677





MUTYH-Associated Polyposis (MAP) MUTYH (2 copies) COLORECTAL OTHER CANCERS /CLINICAL FEATURES

MUTYH (1 copy) Associated Cancer MUTYH (1 copy) COLORECTAL

MUTYH-associated Polyposis syndrome (MAP) (also known as MYH-associated polyposis)

MUTYH-associated Polyposis syndrome (MAP) is a heredi-

tary cancer condition in which patients have high risks for

colorectal cancer, which may be accompanied by large

numbers of adenomatous polyps in the gastrointestinal

system. MAP is unique among the hereditary cancer syn-

dromes included as part of Myriad myRisk™, in that it is

a “recessive” condition. Most hereditary cancer conditions

are “dominant,” meaning that the condition is present in

patients with a mutation in one copy of the gene, inher-

ited from one of their parents. Patients have MAP only if

there are mutations in both of their copies of the MUTYH

gene, one of which is inherited from the patient’s father,

and the other from their mother. Patients with MAP often

have no family history of colorectal cancer, or the only

affected relatives are siblings. This pattern differs from

dominant hereditary cancer conditions (such as FAP/AFAP

and Lynch syndrome) where cancers are seen in multiple

generations.

MAP was first described and linked to the MUTYH gene

(also known as MUTYH) in 3 siblings affected by what

appeared to be the attenuated form of Familial Adeno-

matous Polyposis (FAP/AFAP), but in whom there were no

identifiable APC gene mutations. Instead, it was found that

each of the three siblings with colon cancer and/or multi-

ple colorectal adenomas had mutations in both copies of

the MUTYH gene. MUTYH is a base excision repair (BER)

gene, recognizing and repairing errors that occur during

DNA replication. When both copies of the MUTYH gene

are inactivated by mutations, cells accumulate mistakes in

their DNA, significantly increasing the likelihood that they

will give rise to tumors.

The most significant cancer risk for patients with MAP is

colorectal cancer. Patients with MAP usually have multiple

colorectal adenomas, but colorectal cancers sometimes

arise before any polyps are detected. There is also an

increased risk for small bowel cancer. Some studies have

described a possible increased risk for a wide range of

other cancers and non-cancer findings in patients with

MAP. However, these studies are not conclusive and the

estimated risks are not large. For these reasons, there are

no medical management guidelines to address these risks.

Although the risk for colorectal cancer in patients with

MAP is high, it is possible to reduce this risk with appropri-

ate medical management. Guidelines for the management

of patients with MAP have been developed by the National

Comprehensive Cancer Network (www.nccn.org).

It is estimated that 1% to 2% of the population has a muta-

tion in one copy of the MUTYH gene. These individuals do

not have MAP, but may have a small increased risk for col-

orectal cancer.







MUTYH-Associated Polyposis (MAP)



MUTYH Gene OverviewMUTYH-associated Polyposis syndrome (MAP)1

• Individuals with mutations in both copies of the MUTYH gene have a condition called MUTYH-associated Polypo-sis syndrome (MAP).

• Most patients with MAP have between 10 and 100s of colorectal polyps by a mean age of 50. These polyps are primarily adenomas, leading to a high risk for colorectal cancer. Colon cancer is sometimes diagnosed in individ-uals with no past history of polyps.

• Patients with MAP also have an increased risk for cancer of the small bowel. Although the absolute risk is esti-mated to be only 4%, between 17% and 25% of patients with MAP will have duodenal polyps and consideration of upper endoscopy is recommended. 11% of patients with MAP will have gastric polyps, but there does not appear to be any increased risk for gastric cancer.

• Some studies have described a possible increased risk for a wide range of cancers and non-cancer findings in patients with MAP. However, these studies are not con-clusive and the estimated risks are not large. For these reasons, there are no medical management guidelines to address these risks.

MUTYH Gene Cancer Risk Table

CANCERAGE

RANGECANCER

RISK

RISK FOR GENERAL

POPULATION2

TWO COPIES (Biallelic)

Small Bowel To age 80 5%3 0.2%

Colorectal To age 80 43%–100%1 3.4%

ONE COPY (Monoallelic)

Colorectal To age 80 3.4%–10%4,5 3.4%

MUTYH - Gene Risk Summary / Overview


MUTYH (2 copies) MUTYH-Associated Polyposis (MAP) COLORECTAL OTHER CANCERS / CLINICAL FEATURES

MUTYH (1 copy) MUTYH (1 copy) Associated Cancer COLORECTAL

MUTYH Gene Cancer Risk Management Table

CANCER PROCEDUREAGE TO BEGIN

FREQUENCY

TWO COPIES (Biallelic)

Small Bowel

Upper en-doscopy with side-viewing endoscope3

30 to 35 years

Every 4 years

Colorectal

Colorectal surgical evaluation and counseling3

Based on cancer diag-nosis and/or adenoma number, size and histology

NA

Colonoscopy3 30 yearsEvery 2 to 3 years

ONE COPY (Monoallelic)

Colorectal

Follow general population colorectal can-cer screening guidelines3

50 years Individualized2

REFERENCES: 1. Brand R, et al. MUTYH-Associated Polyposis. In: Pagon RA, et al., editors. GeneReviews. 2012 Available from http://www.ncbi.nlm.nih.gov/books/NBK107219/. PubMed PMID: 23035301. 2. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 3. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 4. Jones N, et al. In-creased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009 137:489-94 PubMed PMID: 19394335. 5. Jenkins MA, et al. Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol Biomarkers Prev. 2006 15:312-4. PMID: 16492921.

• Although the risk for colorectal cancer in patients with MAP is very high, it is possible to reduce this risk with appropriate medical management. Guidelines for the management of patients with MAP have been devel-oped by the National Comprehensive Cancer Network (NCCN). These are listed below. It is recommended that patients with MUTYH mutations and a diagnosis of MAP be managed by a multidisciplinary team with expertise in medical genetics and the care of patients with hereditary gastrointestinal cancer syndromes.

MUTYH (1 copy) Associated Cancer• Individuals with a single MUTYH mutation may have a

small increased risk for colon cancer. This increase in risk seems to be seen most consistently in patients who have a close relative (parent, brother, sister or child) who has had colon cancer, with increases in risk that are roughly equal to those associated with family history alone. Therefore, medical management for patients with a sin-gle MUTYH mutation is based on family history guidelines rather than the genetic test results.

• Individuals with a single MUTYH mutation is considered a carrier for a clinically significant mutation of a recessive condition





Melanoma-Pancreatic Cancer Syndrome (M-PCS) CDKN2A (p16INK4A) MELANOMA PANCREATIC

Melanoma Cancer Syndrome (MCS) CDKN2A (p14ARF), CDK4 MELANOMA PANCREATIC

Melanoma-Pancreatic Cancer Syndrome (M-PCS)/Melanoma Cancer Syndrome (MCS)

Melanoma-Pancreatic Cancer Syndrome (M-PCS) and

Melanoma Cancer Syndrome (MCS) are hereditary cancer

syndromes in which patients have a high risk for melanoma

and possibly pancreatic cancer. M-PCS and MCS were pre-

viously known as Familial Atypical Multiple Mole Melanoma

syndrome (FAMMM), but that name is no longer consid-

ered accurate, since most affected patients do not have

multiple atypical moles.

The CDKN2A gene is used to produce two different pro-

teins, p16INK4a and p14ARF. The name M-PCS is used for

patients with mutations that impact the production of the

protein p16INK4a. Patients with M-PCS have a high risk for

melanoma, and in many cases, a high risk for pancreatic

cancer as well. The name MCS is used for patients with

mutations in the CDKN2A gene that impact the produc-

tion of the protein p14ARF, and for patients with mutations

in the CDK4 gene. Patients with MCS have an increased

risk for melanoma. Patients with MCS may also have an

increased risk for pancreatic cancer, but this is not yet

known.

The proteins produced by the CDKN2A and CDK4 genes

play an important role in regulating the growth of cells.

Cells with mutations that disrupt the normal function of

these proteins lack this growth control, which can lead to

cancer.

Although there is a high risk for melanoma, and possibly

pancreatic cancer, in patients with M-PCS/MCS, it may

be possible to reduce this risk with appropriate medical

management, including increased attention to surveillance

and lifestyle modifications focused on minimizing sun

exposure. Clinical trials are underway to explore the value

of various protocols for the early detection of pancreatic

cancer.







Melanoma-Pancreatic Cancer Syndrome (M-PCS)



CDKN2A (p16INK4a) Gene OverviewMelanoma-Pancreatic Cancer Syndrome1,2,3

• Individuals with CDKN2A (p16INK4a) mutations have

Melanoma-Pancreatic Cancer Syndrome (M-PCS). This

condition has previously been known as Familial Atypical

Multiple Mole Melanoma syndrome (FAMMM).

• Patients with M-PCS have a high risk of developing mel-

anoma. Exact estimates of the melanoma risk associated

with CDKN2A (p16INK4a) mutations vary over a wide

range, with higher risks found in patients who have a pre-

vious family history of melanoma.

• Patients with M-PCS due to mutations in CDKN2A

(p16INK4a) may also have a high risk for pancreatic

cancer. This risk may not be present in all families with

CDKN2A (p16INK4a) Gene Cancer Risk Table

CANCER AGE RANGE CANCER RISK RISK FOR GENERAL POPULATION4

Pancreatic To age 75 Up to 17%1 0.7%

MelanomaTo age 50 14%-50%2,3 0.3%

To age 80 28%-76%2,3 1.6%

CDKN2A (p16INK4a) - Gene Risk Summary / Overview


CDKN2A (p16INK4A) Melanoma-Pancreatic Cancer Syndrome (M-PCS) MELANOMA PANCREATIC

mutations in CDKN2A (p16INK4a), so concern about

pancreatic cancer risk should be higher for patients who

have a family history of this cancer.

• Although there is a high risk for melanoma and pancre-

atic cancer in patients with M-PCS, it may be possible

to reduce this risk with appropriate medical manage-

ment, including increased attention to surveillance and

lifestyle modifications. Guidelines from expert groups

for the management of patients with high risks for these

cancers follow. Since information about the cancer risks

associated with CDKN2A (p16INK4a) mutations is rela-

tively new, and there is uncertainty about the best ways

to reduce these risks, it may be appropriate to interpret

these results in consultation with cancer genetics pro-

fessionals who have expertise in this emerging area of

knowledge.

REFERENCES: 1. Vasen HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000 87:809-11. PMID: 10956390. 2. Bishop DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002 94:894-903. PMID: 12072543. 3. Begg CB, et al. Genes Environment and Melanoma Study Group. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005 97:1507-15. PMID: 16234564. 4. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 5. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pan-creatic cancer. Gut. 2013 62:339-47. PMID: 23135763. 6. Kefford RF et al. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus statement of the Melanoma Genetics Consortium. J Clin Oncol. 1999 17:3245-51. PMID: 10506626. 7. Coit DG et al. NCCN Clinical Practice Guidelines in Oncology®: Melanoma. V 2.2013. October 17. Available at http://www.nccn.org.

CDKN2A (p16INK4a) Gene Cancer Risk Management Table


Pancreatic

Consider available options for pancreatic cancer screening, including the possibility of endoscopic ultrasonography (EUS) and MRI/magnetic resonance cholangiopancreatography (MRCP). It is recommended that patients who are candidates for pancreatic cancer screening be managed by a multidisciplinary team with experience in the screening for pancreatic cancer, preferably within research protocols5

Individualized NA

Melanoma

Education about the importance of skin protection, such as sun avoidance, protective clothing and sunscreen6,7 Infancy Ongoing

Whole body skin exams conducted by the patient or family member6,7 10 years Monthly

Clinical skin exams by an appropriately trained provider, with consideration of whole-body photography and close-up photography of atypical nevi for ongoing comparison6,7

10 yearsEvery 6 to 12 months




CDKN2A (p14ARF) Gene OverviewMelanoma Cancer Syndrome (MCS)1,2,3,4

• Individuals with CDKN2A (p14ARF) mutations have Mel-

anoma Cancer Syndrome (MCS).

• Patients with MCS have a high risk of developing mel-

anoma. There are currently no exact estimates of the

risk associated with CDKN2A (p14ARF) mutations, but

it is believed that melanoma risks are similar to those

for patients with a similar condition due to mutations in

the CDKN2A (p16INK4a) gene. Those risks are provided

below. It is possible that these estimates will change over

time as we learn more about the exact risks associated

with mutations in CDKN2A (p14ARF).

• Patients with MCS due to mutations in CDKN2A (p14ARF)

may also have a high risk for pancreatic cancer, as a high

risk for pancreatic cancer has been observed in some

CDKN2A (p14ARF) Gene Cancer Risk Table


MelanomaTo age 50 14%-50%2,3 0.3%

To age 80 28%-76%2,3 1.6%

Pancreatic To age 75 Elevated risk1,4 0.7%

CDKN2A (p14ARF) - Gene Risk Summary / Overview


CDKN2A (p14ARF) Melanoma Cancer Syndrome (MCS) MELANOMA PANCREATIC

families with mutations in the related gene CDKN2A

(p16INK4a). Concern about pancreatic cancer risk should

be higher for patients who have a family history of this

cancer.

• Although there is a high risk for melanoma, and possi-

bly pancreatic cancer, in patients with MCS, it may be

possible to reduce this risk with appropriate medical

management, including increased attention to surveil-

lance and lifestyle modifications. Guidelines from expert

groups for the management of patients with increased

risks for these cancers are listed below. Since informa-

tion about the cancer risks associated with CDKN2A

(p14ARF) mutations is relatively new, and there is uncer-

tainty about the best ways to reduce these risks, it may

be appropriate to interpret these results in consultation

with cancer genetics professionals who have expertise in

this emerging area of knowledge.

REFERENCES: 1. Vasen HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000 87:809-11. PMID: 10956390. 2. Bishop DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002 94:894-903. PMID: 12072543. 3. Begg CB, et al. Genes Environment and Melanoma Study Group. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005 97:1507-15. PMID: 16234564. 4. Goldstein AM, et al. Melanoma Genetics Consortium (GenoMEL). High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006 66:9818-28. PMID: 17047042. 5. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 6. Kefford RF et al. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus statement of the Melanoma Genetics Consortium. J Clin Oncol. 1999 17:3245-51. PMID: 10506626. 7. Coit DG et al. NCCN Clinical Practice Guidelines in Oncology®: Melanoma. V 2.2013. October 17. Available at http://www.nccn.org.

CDKN2A (p14ARF) Gene Cancer Risk Management Table


Melanoma


Whole-body skin exams conducted by the patient or family member6,7 10 years Monthly




NA NA




CDK4 Gene OverviewMelanoma Cancer Syndrome1,2,3,4,5

• Individuals with CDK4 mutations have Melanoma Cancer

Syndrome (MCS).

• Patients with MCS have a high risk of developing mel-

anoma. There are currently no exact estimates of the

risk associated with CDK4 mutations, but it is believed

that melanoma risks are similar to those for patients

with a similar condition due to mutations in the CDKN2A

(p16INK4a) gene. Those risks are provided below. It is

possible that these estimates will change over time as we

learn more about the exact risks associated with muta-

tions in CDK4.

• Patients with MCS due to mutations in CDK4 may also

have a high risk for pancreatic cancer, as a high risk for

CDK4 Gene Cancer Risk Table


MelanomaTo age 50 14%-50%2,3 0.3%

To age 80 28%-76%2,3 1.6%

Pancreatic To age 75 Elevated risk1,4 0.7%

CDK4 - Gene Risk Summary / Overview


CDK4 Melanoma Cancer Syndrome (MCS) MELANOMA PANCREATIC

pancreatic cancer has been observed in some families

with mutations in the related gene CDKN2A (p16INK4a).

Concern about pancreatic cancer risk should be higher

for patients who have a family history of this cancer.

• Although there is a high risk for melanoma, and possibly

pancreatic cancer, in patients with MCS, it may be possi-

ble to reduce this risk with appropriate medical manage-

ment, including increased attention to surveillance and

lifestyle modifications. Guidelines from expert groups

for the management of patients with increased risks for

these cancers follow. Since information about the cancer

risks associated with CDK4 mutations is relatively new,

and there is uncertainty about the best ways to reduce

these risks, it may be appropriate to interpret these

results in consultation with cancer genetics professionals

who have expertise in this emerging area of knowledge.

REFERENCES: 1. Vasen HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000 87:809-11. PMID: 10956390. 2. Bishop DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002 94:894-903. PMID: 12072543. 3. Begg CB, et al. Genes Environment and Melanoma Study Group. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005 97:1507-15. PMID: 16234564. 4. Goldstein AM, et al. Melanoma Genetics Consortium (GenoMEL). High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006 66:9818-28. PMID: 17047042. 5. Goldstein AM, et al. Genotype-phenotype re-lationships in U.S. melanoma-prone families with CDKN2A and CDK4 mutations. J Natl Cancer Inst. 2000 92:1006-10. PMID: 10861313. 6. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 7. Kefford RF et al. Counseling and DNA testing for individuals perceived to be genetically predisposed to melanoma: A consensus statement of the Melanoma Genetics Consortium. J Clin Oncol. 1999 17:3245-51. PMID: 10506626. 8. Coit DG et al. NCCN Clinical Practice Guidelines in Oncology®: Melanoma. V 2.2013. October 17. Available at http://www.nccn.org.

CDK4 Gene Cancer Risk Management Table


Melanoma


Whole-body skin exams conducted by the patient or family member7,8 10 years Monthly




NA NA





Li-Fraumeni Syndrome

(LFS)TP53 BREAST OVARIAN COLORECTAL ENDOMETRIAL MELANOMA PANCREATIC GASTRIC PROSTATE

OTHER CANCERS / CLINICAL FEATURES

Li-Fraumeni Syndrome (LFS)

Li–Fraumeni syndrome (LFS) was first described by 2

American physicians, Frederick Li and Joseph F. Frau-

meni, Jr. in 1969. This condition was originally thought to

be extremely rare, but there are recent indications that a

significant proportion of breast cancers in women under

age 30 are due to LFS.

It is now known that LFS is due to mutations in the TP53

gene. At one time it was also believed that the CHEK2 gene

was a cause of LFS, but this is no longer believed to be

the case. The TP53 gene is important for maintaining the

quality of DNA in cells. When TP53 mutations are present,

cells accumulate damage to their DNA, which significantly

increases the likelihood that those cells will develop into

cancers.

Individuals with LFS have a high lifetime risk for many dif-

ferent types of cancer, frequently at young ages. The most

common cancers in patients with LFS are premenopausal

female breast cancer, soft tissue and bone sarcomas, adre-

nocortical carcinoma and brain tumors. It is not unusual for

patients with LFS to develop additional primary cancers

after an initial cancer diagnosis.

Although the risk for cancer in patients with LFS is very

high, it may be possible to reduce this risk with appropri-

ate medical management. Guidelines for the management

of patients with LFS have been developed by the National

Comprehensive Cancer Network (www.nccn.org).







Li-Fraumeni Syndrome (LFS)



TP53 - Gene Risk Summary / Overview

TP53 Gene OverviewLi-Fraumeni Syndrome (LFS)1,2

• Individuals with a mutation in TP53 have a condition

called Li-Fraumeni syndrome (LFS).

• Individuals with LFS have a high lifetime cumulative risk

for a wide spectrum of cancers and for developing multi-

ple primary tumors. Cancer risk is heavily biased towards

younger ages, and individuals with LFS often develop

cancer at early ages, with the majority of cancers diag-

nosed under age 45.

• The most common cancers diagnosed in patients with

LFS are premenopausal female breast cancer, soft tissue

and bone sarcomas, adrenocortical carcinoma and brain

tumors. However, the risk for a diverse group of other

cancers is also thought to be increased as detailed in the

Cancer Risk Table below.

• The overall lifetime cancer risk for women is higher than

TP53 Gene Cancer Risk Table



POPULATION3

Overall cancer risk (female)To age 45 Up to 84%5 3.5%

To age 85 Up to 100%5 33.3%

Female Breast To age 80

Greatly increased, with a strong tendency towards very young ages of diagnosis—the large majority of cases occurring before menopause 1,2

10.2%

Overall cancer risk (male and female)

Risk for a second primary cancer of any type after a first cancer diagnosis

Up to 57%6 NA

Overall cancer risk (male)To age 45 Up to 41%5 2.2%

To age 85 Up to 73%5 40.4%

Other - including Adrenocortical Car-cinoma, Choroid Plexus, Soft Tissue Sarcoma, Bone Sarcoma, and Brain

To age 80

Greatly increased, with a strong tendency towards young ages of diagnosis—the large majority of cas-es are diagnosed before age 501,2,5

NA

Ovarian To age 80Elevated risk, with a tendency towards young ages of diagnosis2 1.1%

Gastric To age 80Elevated risk, with a tendency towards young ages of diagnosis2 0.6%

Pancreatic To age 80Elevated risk, with a tendency towards young ages of diagnosis2 1%



TP53Li-Fraumeni Syndrome

(LFS)BREAST OVARIAN COLORECTAL ENDOMETRIAL MELANOMA PANCREATIC GASTRIC PROSTATE

OTHER CANCERS / CLINICAL FEATURES

that for men, mostly due to the very high risk for female

breast cancer. Male breast cancer risk is not thought to

be increased.

• Individuals with LFS are advised to avoid exposure to

ionizing radiation, both in connection with screening and

with therapy, as these exposures can trigger malignancies.

• Although the risk for cancer in patients with LFS is very

high, it may be possible to reduce this risk with appro-

priate medical management. Guidelines for the manage-

ment of patients with LFS have been developed by the

National Comprehensive Cancer Network (NCCN). Since

LFS is a rare and complex condition, it is recommended

that patients with TP53 mutations and a diagnosis of LFS


in the prevention and treatment of the many malignan-

cies for which these patients are at risk.



TP53 - Gene Risk Summary / Overview

TP53 Gene Cancer Risk Management Table


Other including adrenocor-tical carcinoma, sarcomas,

brain tumors, leukemia, lym-phoma, and other cancers, especially those for which there is a past diagnosis in

the family.

Comprehensive physical and neurological exam, and consideration of organ-targeted surveillance. Consider standard and novel screening modalities, preferably within clinical trials1

Childhood, individualized based on patient personal and family history

Annually

Female Breast

Breast awareness—Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self- examination (BSE) may facilitate breast awareness.1

18 years NA

Clinical breast exam1

20 to 25 years, or indi-vidualized to a younger age based on the earliest diagnosis in family

Every 6 to 12 months

Mammography and Breast MRI1

20 to 25 years, or indi-vidualized to a younger age based on the earliest diagnosis in family

Annual


Colorectal Consider colonoscopy1 No later than 25 years Every 2 to 5 years

Other including gastric, ovarian, endometrial, pros-tate and pancreatic cancer.

Comprehensive physical exam, and con-sideration of organ-targeted surveillance. Consider standard and novel screening modalities, preferably within clinical trials1

Individualized based on patient personal and family history

Annually

Melanoma Skin exam1 Individualized Annually

REFERENCES: 1. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 2. Schneider K, Garber J. Li-Fraumeni Syndrome. In: Pagon RA, et al., editors. GeneReviews. 2010 Available From http://www.ncbi.nlm.nih.gov/books/NBK1311/. PubMed PMID: 20301488. 3. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 4. Wong P, Vet al. Prev-alence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology. 2006 130:73-9. PMID: 16401470. 5. Chompret A, et al. p53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000 82:1932-7. PMID: 10864200. 6. Hisada M, et al. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst. 1998 90:606-11. PMID: 9554443.

TP53 Gene Cancer Risk Table (cont.)



POPULATION3

Colorectal To age 80

Elevated risk, with a strong tenden-cy towards young ages of diagno-sis—the median age of diagnosis is estimated to be 411,4

3.4%

Endometrial To age 80Elevated risk, with a tendency towards young ages of diagnosis2 2.3%

Prostate To age 80Elevated risk, with a tendency towards young ages of diagnosis2 13.6%

Other - including non-Melanoma Skin, Lung, Leukemia, Lymphoma,

Esophageal, Neuroblastoma, Thyroid, and Kidney

To age 80Elevated risk, with a tendency towards young ages of diagnosis1,2,5 NA

Melanoma To age 80Elevated risk, with a tendency towards young ages of diagnosis2 1.6%





PTEN Hamartoma Tumor Syndrome (PHTS) PTEN BREAST COLORECTAL ENDOMETRIALOTHER CANCERS /

CLINICAL FEATURES

PTEN Hamartoma Tumor Syndrome (PHTS)

PTEN Hamartoma Tumor Syndrome (PHTS) refers to a set

of conditions caused by inherited mutations in the PTEN

gene. Patients with PTEN gene mutations are at risk for

developing hamartomas throughout the body. Hamarto-

mas are non-cancerous tumors composed of abnormal

formation of tissue of the type normally found in that area

of the body.

Patients with PHTS have a high risk for breast, endometrial

and thyroid cancer. There is also an increased risk for col-

orectal cancer.

A subset of patients with PHTS may have a diagnosis of

other syndromes, such as Cowden Syndrome (CS), Ban-

nayan-Riley-Ruvalcaba Syndrome (BRRS), PTEN-related

Proteus Syndrome or Proteus-like Syndrome. The distinc-

tion between these conditions is based on a wide variety

of other, non-malignant features, such as macrocephaly,

Lhermitte-Duclos disease (a hamartomatous brain tumor),

fibrocystic breast disease, uterine fibroids, goiters, geni-

tourinary abnormalities, overgrowth of parts of the body,

and distinctive skin findings such as trichilemmomas, acral

keratoses and papillomatous papules.

PTEN is an abbreviation for Phosphatase and TENsin

homolog. The PTEN protein functions as a tumor sup-

pressor in cells, normally acting to limit cell growth. In

the absence of appropriate PTEN activity, cells are able

to grow uncontrollably, leading to tumor formation and

the possibility of cancer. PTEN may also play a role in cell

adhesion and migration.

Although patients with PHTS have high risks for cancer, it

is possible to reduce these risks with appropriate medical

management. Guidelines for the management of patients

with PHTS have been developed by the National Compre-

hensive Cancer Network (www.nccn.org).







PTEN Hamartoma Tumor Syndrome (PHTS)




PTEN PTEN Hamartoma Tumor Syndrome (PHTS) BREAST COLORECTAL ENDOMETRIALOTHER CANCERS /

CLINICAL FEATURES

PTEN Gene OverviewPTEN Hamartoma Tumor Syndrome (PHTS)1,2

• Individuals with PTEN mutations have PTEN Hamartoma

Tumor Syndrome (PHTS).

• Individuals with PHTS have a significantly increased risk

for certain cancers, particularly breast, endometrial, col-

orectal and thyroid. These cancers are often diagnosed

at relatively young ages.

• Patients with PHTS often have a wide variety of other,

non-malignant features of the condition, some of which

may require medical attention. Examples are macro-

cephaly, Lhermitte-Duclos disease (a hamartomatous

brain tumor), fibrocystic breast disease, uterine fibroids,

goiters, genitourinary abnormalities, and distinctive skin

findings such as trichilemmomas, acral keratoses and

papillomatous papules.

PTEN Gene Cancer Risk Table


POPULATION3

Female Breast To age 80 25%-50%5,2 10.2%

Thyroid To age 80 3%-10%5,2 1%


Other - Non- malignant features

of PHTSAll ages

As described in the overview above, PHTS is associated with non-malignant clinical features, some of which may require medical intervention as early as infancy5,1,2

NA

Colorectal To age 80 Up to 7%4 3.4%

PTEN - Gene Risk Summary / Overview

• A subset of patients with PHTS may have a diagnosis of

other syndromes, such as Cowden Syndrome (CS), Ban-

nayan-Riley-Ruvalcaba Syndrome (BRRS), PTEN-related

Proteus Syndrome or Proteus-like Syndrome, based on

other clinical features. Some of these conditions have

features that may require intervention in infancy or

childhood.

• Although there are high risks for cancer in patients

with PHTS, these risks can be reduced with appropri-

ate medical management. Guidelines from the National

Comprehensive Cancer Network (NCCN) are listed in

the following tables. Management of patients with PHTS

poses challenges due to the complexity of the condition

and it is recommended that patients with PTEN muta-

tions and a diagnosis of PHTS be managed by a multidis-

ciplinary team with expertise in medical genetics and the

care of patients with hereditary cancer syndromes.




REFERENCES: 1. Eng C. PTEN Hamartoma Tumor Syndrome (PHTS). In: Pagon RA, et al., editors. GeneReviews. 2012 Available from http://www.ncbi.nlm.nih.gov/books/NBK1488/PubMed PMID: 20301661. 2. Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns. 2009 18:13-27. PMID: 18972196. 3. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 4. Heald B, et al. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010 139:1927-33. PMID: 20600018. 5. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 6. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org.

PTEN Gene Cancer Risk Management Table


Female Breast

Breast awareness —Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consis-tent breast self-examination (BSE) may facilitate breast awareness.5

18 years NA


25 years, or individ-ualized to a younger age based on the earliest diagnosis in family

Every 6 to 12 months

Mammography and Breast MRI5

30 to 35 years, or individualized to a younger age based on the earliest diag-nosis in family

Annual


Thyroid Thyroid ultrasound5 18 yearsConsider annually

EndometrialPatient education about endometrial cancer symptoms5 Individualized NA

Consider hysterectomy5 Individualized NA

Other - Non- malignant features of

PHTS

Comprehensive physical/dermatological exam and treatment for man-ifestations as necessary1

18 years or 5 years before the youngest age of a PHTS- related cancer in the family

Annually

General Cancer Risk

Comprehensive physical/dermatological exam and general education about the signs and symptoms of cancer with particular attention to thyroid cancer5

18 years or 5 years before the youngest age of a PHTS- related cancer in the family

Annually

Colorectal Consider colonoscopy5 35 yearsEvery 5 to 10 years

PTEN - Gene Risk Summary / Overview





Peutz-Jeghers Syndrome (PJS)

STK11 BREAST OVARIAN COLORECTAL ENDOMETRIAL PANCREATIC GASTRICOTHER CANCERS /

CLINICAL FEATURES


Peutz-Jeghers Syndrome (PJS) is a hereditary cancer con-

dition in which patients develop hyperpigmented spots

on mucocutaneous surfaces, a distinct form of polyposis

throughout the gastrointestinal system and high risks for a

variety of cancers. The condition was first noted in 1895 in

a pair of twins with pigmentation abnormalities who later

developed intestinal obstructions and breast cancer. In

1921, Dr. Johannes Peutz described a boy with polyps and

abnormal pigmented macules. The syndrome was more

clearly defined by Harold Jeghers, et al. in 1949 with the

description of 10 additional families.

STK11 mutations have been identified in the majority

of patients with PJS. (The gene is also known as LKB1.)

STK11 is a serine/threonine kinase tumor suppressor gene.

Although there are PJS patients in whom it has not been

possible to find an STK11 mutation, no other genes for the

condition have been identified.

PJS is characterized by the presence of a distinct type

of hamartomatous polyp throughout the gastrointestinal

system. The presence of these polyps is associated with a

high risk for cancer, although the precise mechanism is not

known. PJS-type polyps can also cause severe gastroin-

testinal symptoms as early as childhood, due to bleeding,

bowel obstruction, rectal prolapse and intussusception (a

telescoping of a portion of the bowel). Patients with PJS

are likely to have hyperpigmented macules (dark blue or

brown spots) around the mouth, eyes, nose, perianal area

and fingers, particularly during childhood.

Individuals with PJS have a high lifetime risk for many

different types of cancer, both within the gastrointestinal

system and in other organs. These cancers include breast,

colon, pancreatic, gastric, small bowel, ovarian (sex cord

tumors), cervical, testicular and endometrial.

Although the risk for cancer and GI complications in

patients with PJS is very high, it may be possible to reduce

this risk with appropriate medical management. Guidelines

for the management of patients with PJS have been devel-

oped by the National Comprehensive Cancer Network

(www.nccn.org).











STK11 Peutz-Jeghers Syndrome (PJS) BREAST COLORECTAL ENDOMETRIALOTHER CANCERS /

CLINICAL FEATURES

STK11 Gene OverviewPeutz-Jeghers Syndrome1,2,3,4

• Individuals with mutations in the STK11 gene have a con-

dition called Peutz-Jeghers Syndrome (PJS).

• Patients with PJS have high risk for a variety of cancers,

including colorectal, female breast, endometrial, gastric,

pancreatic, small bowel, cervical, testicular, and lung can-

cers. Cancers in patients with PJS are often diagnosed

at much younger ages than typically seen in the general

population.

• Women with PJS have an increased risk for ovarian neo-

plasms, including adenocarcinomas. However, sex cord

tumors are the most common ovarian tumor found in

these patients.

• Patients with PJS are likely to develop hamartomatous

gastrointestinal polyps with a distinctive Peutz-Jeghers

histology. The most common location of these polyps is

the small bowel, but they may also be found in the stom-

ach, colon and nasal passages. Polyps may require treat-

STK11 Gene Cancer Risk Table


Ovarian To age 70 18%-21%1 0.7%

Small Bowel To age 70 13%1,3 0.1%

Testicular To age 70 9%3 0.4%

Female Breast To age 70 45%-50%1 7.3%

Gastric To age 70 29%1,3 0.3%

Pancreatic To age 70 11%-36%1,3 0.5%

Colorectal To age 70 39%1,3 1.9%

Endometrial To age 70 9%1,3 1.6%

Cervical To age 70 10%1,3 0.5%

Lung To age 70 15%-17%1,3 2.6%

STK11 - Gene Risk Summary / Overview

ment due to bleeding with subsequent anemia, recurrent

obstruction and/or intussusception.

• Patients with PJS are likely to develop pigmented spots

around the mouth, eyes, nostrils, anus and on the fingers

during childhood. These spots are usually present by age

5 and often fade during puberty and adulthood.

• Although there are high risks for cancer and other med-

ical problems in patients with PJS syndrome, these risks

can be reduced with appropriate medical management.

Guidelines from the National Comprehensive Cancer

Network (NCCN) are listed in the following tables, and

additional detailed discussions of medical management

options are also available from other sources (see van

Lier MG et al., Am J Gastroenterol. 2010, 105: 1258-64 and

Beggs AD et al. Gut. 2010, 59:975-86). Due to the com-

plexity of the condition it is recommended that patients

with STK11 mutations and a diagnosis of PJS be managed

by a multidisciplinary team with experience in the pre-

vention and treatment of the complications associated

with this condition.




REFERENCES: 1. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 2. McGarrity TJ, et al. Peutz-Jeghers Syndrome. In: Pagon RA, et al., editors. GeneReviews. 2013 Available from http://www.ncbi.nlm.nih.gov/books/NBK1266/. PMID: 20301443. 3. van Lier MG, et al. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010 105:1258-64. PMID: 20051941. 4. Beggs AD, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut. 2010 59:975-86. PMID: 20581245. 5. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 6. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763.

STK11 Gene Cancer Risk Management Table


Ovarian

Pelvic examination1 18 to 20 years Annually

Consider transvaginal ultrasound1 18 to 20 years Annually

Small Bowel Small bowel visualization with CT enterography1

Baseline at 8 to 10 years with follow up as needed, but no later than age 18

Every 2 to 3 years after age 18

TesticularAnnual testicular exam and observation for feminizing changes1 10 years Annually

Female Breast

Clinical breast exam1 25 yearsEvery 6 months

Mammography and Breast MRI1 25 years Annual

Gastric Upper endoscopy1 Late teensEvery 2 to 3 years

Colorectal Colonoscopy1 Late teensEvery 2 to 3 years

PancreaticMagnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound (EUS)1,6 25 to 30 years

Every 1 to 2 years

Endometrial

Pelvic examination1 18 to 20 years Annually

Consider transvaginal ultrasound1 18 to 20 years Annually

Cervical Pap smear1 18 to 20 years Annually

Lung Provide education about symptoms and smoking cessation1 As needed As needed

STK11 - Gene Risk Summary / Overview





Hereditary Diffuse Gastric Cancer (HDGC) CDH1 BREAST COLORECTAL GASTRIC

Hereditary Diffuse Gastric Cancer (HDGC)

Hereditary Diffuse Gastric Cancer (HDGC) is a heredi-

tary cancer syndrome in which patients have a high risk

for the diffuse form of gastric cancer and a high risk for

lobular breast cancer in women. HDGC results from inher-

ited mutations in the CDH1 gene, which codes for the cell

adhesion protein, E-cadherin. So far, CDH1 is the only gene

known to be associated with HDGC.

Individuals with CDH1 mutations have a high risk for dif-

fuse gastric cancer. In contrast to the more common form

of intestinal type gastric cancer, diffuse gastric cancer

typically forms without a distinct mass, making it much

harder to detect with endoscopic screening. The major-

ity of diffuse gastric cancers in individuals with HDGC are

diagnosed under age 40.

Women with HDGC are also at a high risk for lobular breast

cancer. Breast cancer is often diagnosed at relatively young

ages in women with HDGC.

Although the risk for cancer in patients with HDGC is high,

it may be possible to reduce this risk with appropriate

medical management. Guidelines for the management of

patients with HDGC have been developed by the Interna-

tional Gastric Cancer Linkage Consortium (IGCLC).







Hereditary Diffuse Gastric Cancer (HDGC)




CDH1 Hereditary Diffuse Gastric Cancer (HDGC) BREAST COLORECTAL GASTRIC

CDH1 Gene OverviewHereditary Diffuse Gastric Cancer (HDGC)1,2,3,4

• Individuals with mutations in CDH1 have a condition called

Hereditary Diffuse Gastric Cancer syndrome (HDGC).

• Patients with HDGC have a high risk for the diffuse form

of gastric cancer, which is less common than intestinal

type gastric cancer. Diffuse gastric cancer is more dif-

ficult to detect with endoscopic screening, because it

typically forms without a distinct mass. The majority of

gastric cancers in individuals with HDGC are diagnosed

under age 40, with some diagnoses occurring in the mid-

teens.

CDH1 Gene Cancer Risk Table


Female BreastTo age 50 10%3 1.9%

To age 80 39%-52%1,3 10.2%

Gastric To age 80 Up to 80%1,3 0.6%

Colorectal To age 80 Possibly elevated1,2,3 3.4%

CDH1 - Gene Risk Summary / Overview

• Women, but not men, with HDGC have a high risk for

lobular breast cancer.

• It is currently not certain that patients with HDGC have

an increased risk for colon cancer, but there is enough

suspicion of an increased risk to recommend special

screening.

• Guidelines for the medical management of patients with

HDGC have been developed by the International Gastric

Cancer Linkage Consortium (IGCLC). It is recommend-

ed that patients with CDH1 mutations and a diagnosis

of HDGC be managed by a multidisciplinary team with

expertise in medical genetics, gastric surgery, gastroen-

terology, pathology and nutrition.

REFERENCES: 1. Kaurah P, Huntsman DG. Hereditary Diffuse Gastric Cancer. In: Pagon RA, et al., editors. GeneReviews. 2011 Available from http://www.ncbi.nlm.nih.gov/books/NBK1139/. PMID: 20301318. 2. Fitzgerald RC et al. International Gastric Cancer Linkage Consortium. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet. 2010 47:436-44. PMID: 20591882. 3. Pharoah PD, et al. International Gastric Cancer Linkage Consortium. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology. 2001 121:1348-53. PMID: 11729114. 4. Kluijt I, et al. Dutch Working Group on Hereditary Gastric Cancer. CDH1-related hereditary diffuse gastric cancer syndrome: clinical variations and implications for counseling. Int J Cancer. 2012 131:367-76. PMID: 22020549. 5. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012.

CDH1 Gene Cancer Risk Management Table


Female Breast


35 years, or individualized to a younger age based on the earliest diagnosis in family

Every 6 months

Mammography and Breast MRI235 years, or individualized to a younger age based on the earliest diagnosis in family

Annually

Gastric

Treat for Helicobacter pylori infection if present2 Individualized NA

Gastrectomy2 20 years NA

Endoscopy with random biopsies, as well as biopsy of suspicious areas until gastrectomy is performed2 16 years Annually

Colorectal Consider colonoscopy2

40 years, or individualized to a younger age based on the earliest diagnosis in family

Every 3 to 5 years





Juvenile Polyposis Syndrome (JPS) BMPR1A COLORECTAL PANCREATIC GASTRICOTHER CANCERS /

CLINICAL FEATURES

Juvenile Polyposis Syndrome (JPS) Hereditary Hemorrhagic Telangiectasia (HHT)

SMAD4 COLORECTAL PANCREATIC GASTRICOTHER CANCERS /

CLINICAL FEATURES

Juvenile Polyposis Syndrome (JPS)

Juvenile Polyposis Syndrome (JPS) is a hereditary colon cancer condition in which patients develop juvenile pol-yps in the colon, rectum, stomach and small intestine. The designation “juvenile” refers to the type of polyps rather than the age at which they are seen, although patients with JPS will often have polyps at young ages, including infancy. Juvenile polyps are hamartomas, rather than the adenomas that are the more common type of polyp from which colorectal cancers arise. However, individuals with JPS do have an elevated risk for cancer of the colon, and the polyps may also cause obstructions and/or anemia due to bleeding.

JPS is caused by mutations in one of two genes, BMPR1A and SMAD4. The mechanism by which mutations in these genes leads to the development of juvenile polyps, and an increased risk for cancer, is not known. A few patients suspected of having JPS have been found to have muta-tions in other genes, but it is believed that these patients probably have a condition other than JPS.

The most significant cancer risks for patients with JPS are colorectal cancer and gastric cancer. There are smaller risks for small bowel cancer and pancreatic cancer.

JPS can be caused by mutations in either BMPR1A or SMAD4, but there is a key difference in that patients with SMAD4 mutations also have the condition Hereditary Hemorrhagic Telangiectasia (HHT). HHT is associated with a high risk for life-threatening arteriovenous malformations of the lungs, brain and liver, as well as nosebleeds. Not all patients with SMAD4 mutations will have all of the features of HHT, but it is recommended that they all receive com-prehensive screening for the clinical features of HHT.

Although there are high risks for cancer and other com-plications in patients with JPS, many of these risks can be greatly reduced with appropriate medical management. Guidelines for the medical management of patients with JPS have been developed by the National Comprehensive Cancer Network (www.nccn.org).

Juvenile Polyposis Syndrome (JPS)Hereditary Hemorrhagic Telangiectasia (HHT)

Hereditary Hemorrhagic Telangiectasia (HHT)

Hereditary Hemorrhagic Telangiectasia (HHT) is not an inherited cancer syndrome, but patients may receive a diagnosis of HHT as a result of Myriad myRisk™ testing if a mutation is found in the SMAD4 gene, which also is a cause of Juvenile Polyposis Syndrome (JPS).

HHT is a disorder of blood vessel formation in which arte-riovenous malformations (AVMs) form throughout the body. Small AVMs (telangiectasias) are often present on the skin and mucosal surfaces, and are prone to rupture and bleeding. Telangiectasias are most likely to cause clin-ical problems when they are present in the nose and the gastrointestinal (GI) tract. Many patients with HHT are at risk for anemia due to frequent nosebleeds, and/or bleed-ing in the GI tract. Larger AVMs can form in the lungs, brain and liver. These are associated with life-threatening com-plications, most of which can be prevented by appropriate screening and treatment.

There are currently three genes known to be linked to HHT—ENG, ACVRL1 and SMAD4. Of these three genes, only SMAD4 is included as part of Myriad myRisk™, because mutations in SMAD4 are also a cause of the hereditary colon cancer syndrome Juvenile Polyposis Syndrome (JPS). Not all patients with SMAD4 mutations will have all of the features of HHT, but it is recommended that they receive comprehensive screening for the clinical features of HHT.

Although there are high risks for cancer in patients with SMAD4 mutations, and high risks for life-threatening com-plications from the AVMs found in patients with HHT, these risks can be greatly reduced with appropriate medical management. Guidelines are available from the National Comprehensive Cancer Network (NCCN) and the Scientific Advisory Committee of the HHT Foundation, Inc. A list of HHT Centers of Excellence can be found at: http://hht.org/living-with-hht/treatment-centers/

Please use the information in the subsequent pages for a summary of the associated gene mutation. This clinical information can be found as part of the Myriad myRisk™ report for a patient found to have a mutation in that gene. This includes information about specific cancer risks and an overview of medical management guidelines.




BMPR1A Juvenile Polyposis Syndrome (JPS) COLORECTAL PANCREATIC GASTRICOTHER CANCERS /

CLINICAL FEATURES

BMPR1A Gene OverviewJuvenile Polyposis Syndrome (JPS)1,2,3

• Individuals with BMPR1A mutations have Juvenile Polyp-

osis Syndrome (JPS).

• Patients with JPS have a high risk for cancer as a result

of hamartomatous polyps in the gastrointestinal sys-

tem, particularly in the colon, rectum and stomach. The

presence of these polyps is associated with a high risk

for colorectal cancer, and can cause bleeding leading to

anemia.

BMPR1A Gene Cancer Risk Table


Gastric To age 80 Up to 21%3 0.6%

ColorectalTo age 42 20%-25%2 <0.2%

To age 80 40%-50%2,3 3.4%

Small Bowel To age 80 Rare, but elevated2,3 0.2%

Pancreatic To age 80 Rare, but elevated2,3 1%

BMPR1A - Gene Risk Summary / Overview

• Patients with JPS also have an elevated risk for small

bowel and pancreatic cancer.


JPS, these risks can be greatly reduced with appropri-

ate medical management. Guidelines from the National

Comprehensive Cancer Network (NCCN) are listed in the

following tables. It is recommended that patients with

BMPR1A mutations and a diagnosis of JPS be managed

by a multidisciplinary team with expertise in medical

genetics and the care of patients with hereditary gastro-

intestinal cancer syndromes.

REFERENCES: 1. Larsen Haidle J, Howe JR. Juvenile Polyposis Syndrome. In: Pagon RA, et al., editors. GeneReviews. 2011 Available from http://www.ncbi.nlm.nih.gov/books/NBK1469/. PMID: 20301642. 2. Howe JR, et al. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol. 1998 5:751-6. PMID: 9869523. 3. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 4. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012.

BMPR1A Gene Cancer Risk Management Table


Gastric Upper endoscopy3 15 yearsEvery 2 to 3 years

Colorectal

Monitor for rectal bleeding and/or anemia1 15 years or earlier if symptoms are present

Ongoing

Colonoscopy3 15 yearsEvery 2 to 3 years


NA NA


NA NA




SMAD4 - Gene Risk Summary / Overview


SMAD4Juvenile Polyposis Syndrome (JPS)

Hereditary Hemorrhagic Telangiectasia (HHT)COLORECTAL PANCREATIC GASTRIC OTHER

SMAD4 Gene OverviewJuvenile Polyposis Syndrome (JPS) and Hereditary Hem-orrhagic Telangiectasia (HHT)1,2,3,4,5

• Individuals with SMAD4 mutations have both Juvenile

Polyposis Syndrome (JPS) and Hereditary Hemorrhagic

Telangiectasia (HHT).

• Patients with JPS have a high risk for cancer as a result

of hamartomatous polyps in the gastrointestinal sys-

tem, particularly in the colon, rectum and stomach. The

presence of these polyps is associated with a high risk

for colorectal cancer, and can cause bleeding leading to

anemia.

• Patients with JPS also have an elevated risk for small

bowel and pancreatic cancer.

SMAD4 Gene Cancer Risk Table

CANCERAGE

RANGECANCER RISK

RISK FOR GENERAL POPULATION6

Other - Hereditary Hemorrhagic

TelangiectasiaAll ages

HHT is associated with a high risk for life threatening arteriovenous malformations of the lungs, brain and liver as well as nosebleeds4 NA

Gastric To age 80 Up to 21%3 0.6%

ColorectalTo age 42 20%-25%2 <0.2%

To age 80 40%-50%2,3 3.4%

Small Bowel To age 80 Rare, but elevated2,3 0.2%

Pancreatic To age 80 Rare, but elevated2,3 1%

SMAD4 Gene Cancer Risk Management Table


Other - Hereditary Hemorrhagic

Telangiectasia

Multiple screenings recommended, which may include brain MRI, contrast echocardiogram, and chest CT4

Some screenings are recommended in infancy

Varies

Gastric Upper endoscopy3 15 years Every 2 to 3 years

ColorectalMonitor for rectal bleeding and/or anemia1 15 years or earlier if

symptoms are presentOngoing

Colonoscopy3 15 years Every 2 to 3 years


NA NA


NA NA

REFERENCES: 1. Larsen Haidle J, Howe JR. Juvenile Polyposis Syndrome. In: Pagon RA, et al., editors. GeneReviews. 2011 Available from http://www.ncbi.nlm.nih.gov/books/NBK1469/. PMID: 20301642. 2. Howe JR, et al. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol. 1998 5:751-6. PMID: 9869523. 3. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 4. McDonald J, et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011 13:607-16. PMID: 21546842. 5. O’Malley M, et al. The prevalence of hereditary hemor-rhagic telangiectasia in juvenile polyposis syndrome. Dis Colon Rectum 2012 55:886-892. PMID: 22810475. 6. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012.

• This patient also has Hereditary Hemorrhagic Telangi-

ectasia (HHT), which is associated with a high risk for

life-threatening arteriovenous malformations of the

lungs, brain and liver, as well as nosebleeds.


JPS, and high risks for life-threatening complications from

the arteriovenous malformations found in patients with

HHT, these risks can be greatly reduced with appropriate

medical management. Guidelines from the National Com-

prehensive Cancer Network (NCCN) and the Scientific

Advisory Committee of the HHT Foundation are listed

in the following tables. It is recommended that patients

with SMAD4 mutations and diagnoses of JPS and HHT be

managed by a multidisciplinary team with experience in the

prevention and treatment of the complications associated

with these conditions.




Gene-Associated Cancer Risk

CHEK2 Pathogenic mutations in the CHEK2 are associated with increased risks for breast as well as colorectal and pros-tate cancer. Although there are currently no professional society medical management guidelines specific to CHEK2 mutation carriers, it is reasonable to consider available rec-ommendations for patients for similar levels of risk, such as the screening guidelines provided by NCCN for patients with a 20% or higher lifetime breast cancer risk (Bevers et al., 2013), or those for patients believed to be at increased risk for prostate cancer due to family history or ancestry (Presti et al., 2013). PALB2Pathogenic mutations in PALB2 are associated with an increased lifetime risk for breast cancer. Although there are currently no professional society medical management guidelines specific to PALB2 mutation carriers, it is reason-able to consider available recommendations for patients for similar levels of risk, such as the screening guidelines provided by NCCN for patients with a 20% or higher lifetime breast cancer risk (Bevers et al., 2013). PALB2 is also associated with inherited risks for pancreatic cancer. Although there are as yet no precise estimates of this risk, the Cancer of the Pancreas Screening Consortium (CAPS) provides a pancreatic cancer screening protocol for con-sideration in patients with pathogenic mutations in PALB2 and a first-degree relative with pancreatic cancer (Canto et al., 2013). ATMGene for the recessive condition Ataxia Telangiectasia. In the heterozygous state, pathogenic mutations in ATM are associated with an increased risk for breast cancer. Although there are currently no professional society med-ical management guidelines specific to heterozygous ATM mutation carriers, it is reasonable to consider available rec-ommendations for patients for similar levels of risk, such as the screening guidelines provided by NCCN for patients with a 20% or higher lifetime breast cancer risk (Bevers et al., 2013). Mutations in ATM have also been linked to an increased risk for pancreatic cancer, and consideration of the CAPS pancreatic cancer screening protocol may be appropriate in some cases (Roberts et al., 2011; Canto et al., 2013).

NBNGene for the recessive condition Nijmegen Breakage Syndrome (NBS). In the heterozygous state, pathogenic mutations in NBN are associated with an increased risk for breast and prostate cancer. Although there are currently no professional society medical management guidelines spe-cific to heterozygous NBN mutation carriers, it is reason-able to consider available recommendations for patients for similar levels of risk, such as the screening guidelines provided by NCCN for patients with a 20% or higher life-time breast cancer risk (Bevers et al., 2013), or those for patients believed to be at increased risk for prostate can-cer due to family history or ancestry (Presti et al., 2013). BARD1, BRIP1, RAD51C and RAD51DFour genes recently identified as having significant asso-ciations with increased risks for breast and/or ovarian cancer. Pathogenic mutations in these genes have been identified in patients whose personal and family histories are consistent with Hereditary Breast and Ovarian Cancer (HBOC), but who do not have detectable in BRCA1 and BRCA2. Information on the cancer risks associated with mutations in these genes is still evolving, but there is suf-ficient evidence in the current literature to justify consid-eration of modified medical management to reduce breast and ovarian cancer risk for mutation carriers. Mutations in BRIP1 and RAD51C are believed to be associated with increased risks for both breast and ovarian cancer. To date, BARD1 has only been linked to an increased risk for breast cancer, and RAD51D only to an increased risk for ovarian cancer. There are currently no professional soci-ety recommendations for modifying medical management guidelines for patients with mutations in these genes, and breast cancer risk estimates do not yet cross the 20% life-time threshold at which NCCN provides specific guidelines for increased surveillance (Bevers et al., 2013). However, the increases in breast and/or ovarian cancer risk warrant consideration of modifying standard population screening guidelines by starting screening at younger ages and/or performing screening at younger ages. In some cases, it may be appropriate to consider additional strategies, such as chemoprevention or risk-reducing surgery, particularly for ovarian cancer risk reduction.

Gene-Associated Cancer Risk

Syndrome Gene Cancer SitePALB2-Associated Cancer Risk PALB2 BREAST PANCREATIC

CHEK2-Associated Cancer Risk CHEK2 BREAST COLORECTAL PROSTATE

ATM-Associated Cancer Risk ATM BREAST PANCREATIC

NBN-Associated Cancer Risk NBN BREAST PROSTATE

BARD1-Associated Cancer Risk BARD1 BREAST

BRIP1-Associated Cancer Risk BRIP1 BREAST OVARIAN

RAD51C-Associated Cancer Risk RAD51C BREAST OVARIAN

RAD51D-Associated Cancer Risk RAD51D OVARIAN



PALB2 - Gene Risk Summary / Overview


PALB2 PALB2-Associated Cancer Risk BREAST PANCREATIC

PALB2 Gene OverviewPALB2-associated Cancer Risk1,2,3,4,5

• Women with PALB2 mutations have a high risk for breast

cancer.

• PALB2 mutations have been found in families with 2 or

more cases of pancreatic cancer in close relatives, indi-

cating that there is an increased risk for pancreatic can-

cer in men and women with PALB2 mutations. The exact

risk is unknown.

• PALB2 mutations have been found in families with cases

of male breast cancer, indicating that there may be an

PALB2 Gene Cancer Risk Table


Female Breast To age 80 20-40%1,2,3 10.2%

Pancreatic To age 80 Elevated risk4,5 1%

Male Breast To age 80 Elevated risk1 0.1%

PALB2 Gene Cancer Risk Management Table


Female Breast

Currently there are no specific medical management guidelines for breast cancer risk in mutation carriers. However, the increase in risk warrants consideration of breast cancer risk reduction strategies, as well as modification of standard population screening recommendations8,9

Individualized NA

Consider breast MRI in addition to mammography8,9 30 years Annually

Breast awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness9

Individualized NA

Clinical breast exam9 30 yearsEvery 6 to 12 months

Pancreatic


Individualized NA

Male Breast

Currently there are no specific medical management guidelines for breast cancer risk in mutation carriers. However, the increase in risk warrants consideration of options for male breast cancer screening, such as patient breast awareness education, clinical breast exams, and mammography, particularly for men with gynecomastia.8,9

Individualized NA

REFERENCES: 1. Casadei S, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011 71:2222-9. PMID: 21285249. 2. Erkko H, et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007 446:316-9. PMID: 17287723. 3. Rahman N, et al. Breast Cancer Susceptibility Collaboration (UK). PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007 39:165-7. PMID: 17200668. 4. Jones S, et al. Ex-omic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009 324:217. PMID: 19264984. 5. Slater EP, et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet. 2010 78:490-4. PMID: 20412113 6. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 7. Canto MI, et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763. 8. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 9. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org. 10. Reid S, et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007 39:162-4. PMID: 17200671.

increased risk for male breast cancer in some men with

PALB2 mutations. The exact risk is unknown.

• Currently there are no widely-accepted guidelines for the

medical management of men and women with PALB2

mutations. Options based on guidelines for other condi-

tions which similarly increase the risk for these cancers

are listed in the following tables. Since information about

the cancer risks associated with PALB2 mutations is rel-

atively new, and there is uncertainty about the best ways

to reduce these risks, it may be appropriate to interpret a

positive gene mutation in consultation with cancer genet-

ics professionals who have expertise in this emerging area

of knowledge.




CHEK2 - Gene Risk Summary / Overview


CHEK2 CHEK2-Associated Cancer Risk BREAST COLORECTAL PROSTATE

CHEK2 Gene Overview

CHEK2-associated Cancer Risk1,2,3,4,5,6,7

• Men and women with CHEK2 mutations have an increased

risk for breast and colorectal cancer. Men with CHEK2

mutations also have an increased risk for prostate cancer.

• Estimates of cancer risk for men and women with CHEK2

mutations vary widely and are strongly influenced by

family history. In cases where there is no family history

of one of these cancers, the risk for a patient with a

CHEK2 mutation may be lower than in cases where that

cancer has been diagnosed in one or more close rela-

tives. Therefore, the family history of a patient should

be considered when deciding on the most appropriate

strategies to manage cancer risk, with more aggressive

strategies targeted to patients with significant family his-

tories of related cancers.

CHEK2 gene Cancer Risk Table


POPULATION8

Female Breast

To age 80 23%-48%1,2,3,4 10.2%

Second breast cancer within 25 years of a first breast cancer diagnosis

Up to 25%4 6.9%

Colorectal To age 80 7.2%-9.5%7 3.4%

Prostate To age 80 24%-44%6 13.6%

Male Breast To age 80 0.4%-1%5 0.1%

• Some studies have described a possible increased risk

for a wide range of cancers in patients with CHEK2

mutations, including leukemia, lymphoma, gastric cancer,

thyroid cancer and other malignancies. However, these

studies are not conclusive and there are no medical man-

agement guidelines to address these possible risks.

• Currently there are no widely accepted guidelines for the

medical management of men and women with CHEK2


tions which similarly increase the risk for these cancers

are listed in the following tables. Since information about

the cancer risks associated with CHEK2 mutations is rel-

atively new, and there is uncertainty about the best ways


a positive gene mutation in consultation with cancer

genetics experts in this emerging area of knowledge.




CHEK2 - Gene Risk Summary / Overview

CHEK2 Gene Cancer Risk Management Table


Female Breast


Individualized NA


Breast awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness11

Individualized NA


Colorectal

Currently there are no specific medical management guidelines for colorectal cancer risk in mutation carriers. However, the increase in risk warrants consideration of modifying standard colorectal cancer population screening recommendations by starting screening at younger ages and/or performing screenings at greater frequency.13

Individualized NA

Prostate


40 years Annually

Male Breast

Currently there are no specific medical management guidelines for breast cancer risk in mutation carriers. However, the increase in risk warrants consideration of options for male breast cancer screening, such as patient breast awareness education, clinical breast exams, and mammography, particularly for men with gynecomastia.10,11

Individualized NA

REFERENCES: 1. Weischer et al. CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol. 2008 26: 542-8. PMID: 18172190. 2. CHEK2 Breast Cancer Case-Control Consortium. CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet. 2004 74:1175-82. PMID: 15122511. 3. Weischer M, et al. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol. 2012 30:4308-16. PMID: 23109706. 4. Meijers-Heijboer H, et al. CHEK2-Breast Cancer Consortium. Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 muta-tions. Nat Genet. 2002 31:55-9. PMID: 11967536. 5. Wasielewski M, et al. CHEK2 1100delC and male breast cancer in the Netherlands. Breast Cancer Res Treat. 2009 116:397-400. PMID: 18759107. 6. Cybulski C, et al. A large germline deletion in the CHEK2 kinase gene is associated with an increased risk of prostate cancer. J Med Genet. 2006b :863-6. PMID: 17085682. 7. Xiang HP, et al. Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility. Eur J Cancer. 2011 47:2546-51. PMID: 21807500. 8. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 9. Burt RW et al. NCCN Clinical Practice Guidelines in Oncology® Colorectal Cancer Screening. V 2.2013. July 1. Available at http://www.nccn.org. 10. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk As-sessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 11. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org. 12. Presti, JC et al. NCCN Clinical Practice Guidelines in Oncology®: Prostate Cancer Early Detection. V 2.2012. May 2. Available at http://www.nccn.org.




ATM - Gene Risk Summary / Overview


ATM ATM-Associated Cancer Risk BREAST PANCREATIC

ATM Gene OverviewATM-associated Cancer Risk1,2,3,4

• Women with ATM mutations have an increased risk for

breast cancer, particularly at young ages.

• ATM mutations have been found in families with two or

more cases of pancreatic cancer in close relatives, indi-

cating that there is an increased risk for pancreatic can-

cer in men and women with ATM mutations. The exact

risk is unknown.

• There have been studies to investigate the possibility

that patients with ATM mutations have an increased risk

ATM Gene Cancer Risk Table


Female Breast

To age 50 Up to 9%3 1.9%

To age 80 17%-52%1,2,3 10.2%

Pancreatic To age 80 Elevated risk4 1%

ATM Gene Cancer Risk Management Table


Female Breast


Individualized NA


Breast awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness.8

Individualized NA


Pancreatic


Individualized NA

REFERENCES: 1. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006 25:5906-11. PMID: 16998505. 2. Swift M, et al. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991 325):1831-6. PMID: 1961222 3. Thompson D, et al. Cancer risks and mortality in heterozygous ATM mutation carriers. J Natl Cancer Inst. 2005 97:813-22. PMID: 15928302. 4. Roberts NJ, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov. 2012 2:41-6. PMID: 22585167. 5. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 6. Canto MI, et al. International Cancer of the Pan-creas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut. 2013 62:339-47. PMID: 23135763. 7. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 8. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org. 9. Gatti R. Ataxia-Telangiectasia. In: Pagon RA, et al., editors. GeneReviews. 2010 Available from http://www.ncbi.nlm.nih.gov/books/NBK26468/. PMID: 20301790.

for a wide range of cancers other than breast and pan-

creatic cancer, but the data for these are not conclusive

at this time.

• Currently there are no widely accepted guidelines for

the medical management of men and women with ATM

mutations. Options based on guidelines for other con-

ditions which similarly increase the risk for the relevant

cancers are listed in the following tables. Since informa-

tion about the cancer risks associated with ATM muta-

tions is relatively new, and there is uncertainty about the

best ways to reduce these risks, it may be appropriate

to interpret a positive gene mutation in consultation

with cancer genetics experts in this emerging area of

knowledge.




NBN - Gene Risk Summary / Overview


NBN NBN-Associated Cancer Risk BREAST PROSTATE

NBN Gene OverviewNBN-associated Cancer Risk1,2,3,4,5

• Mutations in the NBN gene are thought to lead to an

increased risk for breast cancer in women, and prostate

cancer in men.

• NBN mutations are most common in patients of Slavic

ancestry, where a single founder mutation (c.657_661del)

is estimated to be present in 1 of 167 individuals. Current

female breast cancer and male prostate cancer risk esti-

mates are based primarily on studies of individuals of

Eastern European ancestry with this specific mutation,

and may not apply to other NBN mutations or patients

of other ancestries.

• It has been suggested that patients with NBN mutations

have an increased risk for cancers other than breast and

NBN Gene Cancer Risk Table


Female Breast To age 80 Up to 30%1,2 10.2%

Prostate To age 80 Increased risk3,5 13.6%

NBN Gene Cancer Risk Management Table


FemaleBreast

Currently there are no specific medical management guidelines for breast cancer risk in mutation carriers. However, the increase in risk warrants consideration of breast cancer risk reduction strategies, as well as modification of standard population screening recommendations by starting screening at younger ages and/or performing screenings at greater frequency.8,9

Individualized NA

ProstateStart risk and benefit discussion about offering baseline digital rectal examination (DRE) and Prostate Specific Antigen (PSA), incorporating information about increased prostate cancer risk7

40 years Annually

REFERENCES: 1. Steffen J, et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer. 2006 119:472-5. PMID: 16770759. 2. Zhang B, et al. Genetic variants associated with breast-cancer risk: comprehensive research synopsis, meta-analysis, and epidemiological evidence. Lancet Oncol. 2011 12:477-88. PMID: 21514219. 3. Cybulski C, et al. An inherited NBN mutation is associated with poor prognosis prostate cancer. Br J Cancer. 2013 108:461-8. PMID: 23149842. 4. Concannon P, Gatti R. Nijmegen Breakage Syndrome. In: Pagon RA, et al. , editors. GeneReviews. 2011 Available from http://www.ncbi.nlm.nih.gov/books/NBK1176/. PMID: 20301355. 5. Cybulski C, et al. NBS1 is a prostate cancer susceptibility gene. Cancer Res. 2004 64:1215-9. PMID: 14973119. 6. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 7. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assess-ment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 8. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org. 9. Presti, JC et al. NCCN Clinical Practice Guidelines in Oncology®: Prostate Cancer Early Detection. V 2.2012. May 2. Available at http://www.nccn.org.

prostate cancer. In particular, there is evidence for an

association with pediatric leukemias and lymphomas.

The data for this are not conclusive at this time and there

are no current medical management recommendations

associated with pediatric cancer risk for carriers of NBN

mutations.

• Currently there are no widely accepted guidelines for

the medical management of men and women with NBN


tions which moderately increase the risk for the relevant

cancers are listed in the following tables. Since informa-

tion about the cancer risks associated with NBN muta-


best ways to reduce these risks, it may be appropriate

to interpret a positive gene mutation in consultation

with cancer genetics experts in this emerging area of

knowledge.




BARD1 - Gene Risk Summary / Overview


BARD1 BARD1-Associated Cancer Risk BREAST

BARD1 Gene Overview

BARD1-associated Cancer Risk1,2,3

• BARD1 mutations have been found in families suspected

of having a form of Hereditary Breast and Ovarian Cancer

syndrome (HBOC), but without detectable mutations in

BRCA1 or BRCA2, with almost all of the mutations found

in patients with breast cancer. Therefore, it is believed

that women with BARD1 mutations have an increased risk

for breast cancer. There is not sufficient evidence at this

time to say that there is also an increased risk for ovarian

cancer in women with BARD1 mutations.

BARD1 Gene Cancer Risk Table


Female Breast To age 80 Elevated risk1,2 10.2%

BARD1 Gene Cancer Risk Management Table


FemaleBreast

Currently there are no specific medical management guidelines for breast cancer risk in mutation carriers. However, the possibility of an increased risk for breast cancer warrants consideration of individualized breast cancer risk reduction strategies, as well as the modification of standard population screening recommendations by starting screening at younger ages and/or performing screenings at greater frequency.5,6

Individualized NA

REFERENCES: 1. De Brakeleer S, et al. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum Mutat. 2010 31:E1175-85. PMID: 20077502. 2. Ratajska M, et al. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res Treat. 2012 131:89-97. PMID: 21344236. 3. Sabatier R, et al. BARD1 homozygous deletion, a possible alternative to BRCA1 mutation in basal breast cancer. Genes Chromosomes Cancer. 2010 49:1143-51. PMID: 20842729. 4. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 5. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 6. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org.

• At this time, there are no known cancer risks for men due

to mutations BARD1.

• There are currently no widely accepted guidelines for the

medical management of women with BARD1 mutations,

and the exact breast cancer risk is not known. Medical

management options based on other conditions which

increase the risk of breast cancer are listed in the follow-

ing tables. Since information about the cancer risks asso-

ciated with BARD1 mutations is relatively new, and there

is uncertainty about the best ways to reduce these risks,

it may be appropriate to interpret a positive gene muta-

tion in consultation with cancer genetics professionals

who have expertise in this emerging area of knowledge.




BRIP1 - Gene Risk Summary / Overview


BRIP1 BRIP1-Associated Cancer Risk BREAST OVARIAN

BRIP1 Gene OverviewBRIP1-associated Cancer Risk1,2

• Women with BRIP1 mutations are believed to have a sig-

nificantly increased risk for ovarian cancer and a moder-

ately increased risk for breast cancer.


to BRIP1 mutations.

• The ovarian cancer risk for women with BRIP1 muta-

tions has been calculated from studies of a single

mutation identified in patients of Icelandic ancestry

(c.2040_2041insTT) and a single mutation identified in

patients of Spanish ancestry (c.1702_1703del). Ovarian

cancer risk was increased 8-fold in the Icelandic patients,

but a much larger increase in risk was calculated for

the Spanish patients. These estimates may not apply

BRIP1 Gene Cancer Risk Table


Ovarian To age 80 8.3%, or higher1 1.1%

Female Breast To age 80 10%-20%, or higher1,2 10.2%

BRIP1 Gene Cancer Risk Management Table


Ovarian

Currently there are no specific medical management guide-lines for ovarian cancer risk in mutation carriers. However, the increase in risk warrants consideration of individualized ovarian cancer risk reduction strategies using currently avail-able options, such as surveillance, risk-reducing surgery and chemoprevention.4

Individualized NA

FemaleBreast

Currently there are no specific medical management guide-lines for breast cancer risk in mutation carriers. However, the possibility of an increased risk for breast cancer warrants consideration of individualized breast cancer risk reduction strategies, as well as the modification of standard population screening recommendations by starting screening at young-er ages and/or performing screenings at greater frequency.4,5

Individualized NA

REFERENCES: 1. Rafnar T, et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet. 2011 43:1104-7. PMID: 21964575. 2. Seal S, et al. Breast Cancer Susceptibility Col-laboration (UK). Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006 38:1239-41. PMID: 17033622. 3. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 4. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 5. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org. 6. Alter BP, Kupfer G. Fanconi Anemia. In: Pagon RA, et al., editors. GeneReviews. 2013 Available from http://www.ncbi.nlm.nih.gov/books/NBK1401/. PMID: 20301575.

to patients of other ancestries, or to other mutations in

BRIP1.

• There is uncertainty about the increase in breast cancer

risk for women with BRIP1 mutations, with estimates

ranging from no increase in risk, to a 2-fold increased

risk, or even an increased risk as high as 12-fold.

• There are currently no widely accepted guidelines for the

medical management of women with BRIP1 mutations.

Options based on guidelines for other conditions which

increase the risk for ovarian and breast cancer are listed in

the following tables. Since information about the cancer

risks associated with BRIP1 mutations is relatively new,

and there is uncertainty about the best ways to reduce

these risks, it may be appropriate to interpret a posi-

tive gene mutation in consultation with cancer genetics

experts in this emerging area of knowledge.




RAD51C - Gene Risk Summary / Overview


RAD51C RAD51C-Associated Cancer Risk BREAST OVARIAN

RAD51C Gene OverviewRAD51C-associated Cancer Risk1,2,3

• Women with RAD51C mutations have an increased risk

for ovarian cancer. Although the actual increase in risk

is currently estimated to be moderate in size, there are

some indications that the risk for ovarian cancer might

be higher in families in which there is a past history of

ovarian cancer.

• Women with RAD51C mutations may have an increased

risk for breast cancer. Evidence for this increased risk for

female breast cancer is strongest in families where there

is a past history of both breast and ovarian cancer.

RAD51C Gene Cancer Risk Table


Ovarian To age 80 6.5% or higher1,2,3 1.1%

Female Breast To age 80 Possibly elevated1 10.2%


to mutations in RAD51C.

• Currently there are no widely-accepted guidelines for the

medical management of women with RAD51C mutations.

Options based on guidelines for other conditions which

moderately increase the risk for ovarian and breast can-

cer are listed in the following tables. Since information

about the cancer risks associated with RAD51C muta-


best ways to reduce these risks, it may be appropriate to

interpret a positive gene mutation in consultation with

cancer genetics experts in this emerging area of knowl-

edge.

REFERENCES: 1. Meindl A, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010 42:410-4. PubMed PMID: 20400964. 2. Loveday C, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet. 2012 44:475-6. PMID: 22538716. 3. Pelttari LM, et al. RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet. 2011 20:3278-88. PMID: 21616938. 4. Surveillance Research Program, National Cancer Institute SEER*Stat soft-ware (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 5. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org. 6. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org. 7. Vaz F, et al. Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet. 2010 42:406-9. PMID: 20400963.

RAD51C Gene Cancer Risk Management Table


Ovarian

Currently there are no specific medical management guidelines for ovarian cancer risk in mutation carriers. However, the increase in risk warrants consideration of individualized ovarian cancer risk reduction strategies using currently available options, such as surveillance, risk-reducing surgery and chemoprevention.5

Individualized NA

FemaleBreast

Currently there are no specific medical management guidelines for breast cancer risk in mutation carriers. However, the possibility of an increased risk for breast cancer warrants consideration of individualized breast cancer risk reduction strategies, as well as the modification of standard population screening recommendations by starting screening at younger ages and/or performing screenings at greater frequency.5,6

Individualized NA




RAD51D - Gene Risk Summary / Overview


RAD51D RAD51D-Associated Cancer Risk OVARIAN

RAD51D Gene OverviewRAD51D-associated Cancer Risk1,2,3

• Women with RAD51D mutations have an increased risk

for ovarian cancer.


to mutations in RAD51D.

• Currently there are no widely-accepted guidelines for

the medical management of women with RAD51D muta-

tions. Options based on guidelines for other conditions

RAD51D Gene Cancer Risk Table


Ovarian To age 80 Up to 7%3 1.1%

RAD51D Gene Cancer Risk Management Table


Ovarian

Currently there are no specific medical management guidelines for ovarian cancer risk in mutation carriers. However, the increase in risk warrants consideration of individualized ovarian cancer risk reduction strategies using currently available options, such as surveillance, risk-reducing surgery and chemoprevention.5

Individualized NA

REFERENCES: 1. Thompson ER, et al. Analysis of RAD51D in Ovarian Cancer Patients and Families with a History of Ovarian or Breast Cancer. PLoS One. 2013 8::e54772. PMID: 23372765. 2. Wickramanyake A, et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012 127:552-5. PMID: 22986143. 3. Loveday C, et al. Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet. 2012 44:475-6. PMID: 22538716. 4. Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) V 8.0.1, Nov 19, 2012. 5. Daly M et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org.

which moderately increase the risk for ovarian cancer are

listed in the following tables. Since information about the

cancer risks associated with RAD51D mutations is rela-

tively new, and there is uncertainty about the best ways


a positive gene mutation in consultation with cancer

genetics experts in this emerging area of knowledge.




SupplementalResources



82 Overview of Result

90 myVision™: Variant Classification Program

92 Myriad myRisk™ Hereditary Cancer Technical Specifications

94 Lab Process

95 Technology FAQs

Supplemental Resources



4

The revolutionary new report presents the myRisk Genetic Result first and clear guideline-based management considerations on subsequent pages

The and symbols indicate whether a

clinically significant mutation is identified.

If positive, the genetic mutation is detailed

with appropriate nomenclature and its

clinical and functional significance

is presented.

myRiskTM Genetic Result

CONFIDENTIAL



Physician Name, MD Myriad Healthcare Partners 320 Wakara Way Salt Lake City, UT 84108

SPECIMEN

Specimen Type: Buccal Draw Date: Jun 8, 2014 Accession Date: Jun 9, 2014 Report Date: Jun 30, 2014

PATIENT

Name: Patient Name Date of Birth: Jan 12, 1970 Patient ID: 1144 Gender: Female Accession #: 00001144-BLD Requisition #: 000000ORDERING PHYSICIAN: Physician Name, MD

myRisk Genetic Result: Page 1 of 2



Details About Non-Clinically Significant Variants: All individuals carry DNA changes (i.e., variants) and most variants do not increase an individual’s risk of cancer or other diseases. When identified, variants of uncertain significance (VUS) are reported. Likely benign variants (Favor Polymorphisms) and benign variants (Polymorphisms) are not reported and available data indicate that these variants most likely do not cause increased cancer risk. Present evidence does not suggest that non-clinically significant variant findings be used to modify patient medical management beyond what is indicated by the personal and family history and any other significant clinical findings.

Variant Classification: Myriad’s myVision™ Variant Reclassification Program continuously performs ongoing evaluations of variant classifications. In certain cases, healthcare providers may be contacted for more clinical information or to arrange family testing to aid in variant classification. When new evidence about a variant is identified, that information will automatically be made available to the healthcare provider through an amended report.


GENE MUTATION INTERPRETATION

BRCA1c.68_69del (p.Glu23Valfs*17)Heterozygous

HIGH CANCER RISK This patient has Hereditary Breast and Ovarian Cancer (HBOC) syndrome.

DETAILS ABOUT: BRCA1 c.68_69del (p.Glu23Valfs*17): NM_007294.3; AKA: 187delAG

Functional Significance: Deleterious – Abnormal Protein Production and/or Function The heterozygous germline BRCA1 mutation c.68_69del is predicted to result in the premature truncation of the BRCA1 protein at amino acid position 39 (p.Glu23Valfs*17).

Clinical Significance: High Cancer RiskThis mutation is associated with increased cancer risk and should be regarded as clinically significant.


myRisk Genetic Result

CONFIDENTIAL




SPECIMEN


PATIENT


myRisk Genetic Result: Page 1 of 2






GENE MUTATION INTERPRETATION

BRCA1c.68_69del (p.Glu23Valfs*17)Heterozygous

HIGH CANCER RISK This patient has Hereditary Breast and Ovarian Cancer (HBOC) syndrome.

DETAILS ABOUT: BRCA1 c.68_69del (p.Glu23Valfs*17): NM_007294.3; AKA: 187delAG

Functional Significance: Deleterious – Abnormal Protein Production and/or Function The heterozygous germline BRCA1 mutation c.68_69del is predicted to result in the premature truncation of the BRCA1 protein at amino acid position 39 (p.Glu23Valfs*17).

Clinical Significance: High Cancer RiskThis mutation is associated with increased cancer risk and should be regarded as clinically significant.





CONFIDENTIAL

© 2014, Myriad Genetic Laboratories, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 800-469-7423 FX: 801-584-3615 myRisk Genetic Result: Page 1 of 2


GENE VARIANT(S) OF UNCERTAIN SIGNIFICANCE INTERPRETATION

PALB2 T1099K (3296C>A)UNCERTAIN CLINICAL SIGNIFICANCE There are currently insufficient data to determine if these variants cause increased cancer risk



ADDITIONAL FINDINGS: VARIANT(S) OF UNCERTAIN SIGNIFICANCE (VUS) IDENTIFIED

Indication for Testing: It is our understanding that this individual was identified for testing due to a personal or family history suggestive of a hereditary predisposition for cancer.

Associated Cancer Risks and Clinical Management: Please see the “Cancer Risk and Management Tool” associated with this report for a summary of cancer risk and professional society medical management guidelines that may be useful in developing a plan for this patient based on test results and reported personal and/or family history, if applicable. Testing of other family members may assist in the interpretation of this patient’s test result.

Analysis Description: The Technical Specifications summary (www.MyriadPro.com) describes the analysis, method, performance, nomenclature, and interpretive criteria of this test. *The classification and interpretation of all variants identified in this assay reflects the current state of scientific understanding at the time this report was issued, and may change as new scientific information becomes available.

Please contact Myriad Professional Support at 1-800-469-7423 to discuss any questions regarding this result.

ADDITIONAL INFORMATION

GENES ANALYZED*

APC CDKN2A1 PMS2

ATM CHEK2 PTEN

BARD1 EPCAM 2 TP53

BMPR1A MLH1 RAD51C

BRCA1 MSH2 RAD51D

BRCA2 MSH6 SMAD4

BRIP1 MUTYH STK11

CDH1 NBN

CDK4 PALB2Unless otherwise noted sequencing and large rearrangement analyses were performed on the above genes. Other genes not analyzed with this test may also be associated with cancer. 1 Analysis of p16INK4a and p14ARF. 2 Large rearrangement only.



SPECIMEN


PATIENT




CONFIDENTIAL

© 2014, Myriad Genetic Laboratories, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 800-469-7423 FX: 801-584-3615 myRisk Genetic Result: Page 1 of 2


GENE VARIANT(S) OF UNCERTAIN SIGNIFICANCE INTERPRETATION

PALB2 T1099K (3296C>A)UNCERTAIN CLINICAL SIGNIFICANCE There are currently insufficient data to determine if these variants cause increased cancer risk




Indication for Testing: It is our understanding that this individual was identified for testing due to a personal or family history suggestive of a hereditary predisposition for cancer.

Associated Cancer Risks and Clinical Management: Please see the “Cancer Risk and Management Tool” associated with this report for a summary of cancer risk and professional society medical management guidelines that may be useful in developing a plan for this patient based on test results and reported personal and/or family history, if applicable. Testing of other family members may assist in the interpretation of this patient’s test result.

Analysis Description: The Technical Specifications summary (www.MyriadPro.com) describes the analysis, method, performance, nomenclature, and interpretive criteria of this test. *The classification and interpretation of all variants identified in this assay reflects the current state of scientific understanding at the time this report was issued, and may change as new scientific information becomes available.


ADDITIONAL INFORMATION

GENES ANALYZED*

APC CDKN2A1 PMS2

ATM CHEK2 PTEN

BARD1 EPCAM 2 TP53

BMPR1A MLH1 RAD51C

BRCA1 MSH2 RAD51D

BRCA2 MSH6 SMAD4

BRIP1 MUTYH STK11

CDH1 NBN

CDK4 PALB2Unless otherwise noted sequencing and large rearrangement analyses were performed on the above genes. Other genes not analyzed with this test may also be associated with cancer. 1 Analysis of p16INK4a and p14ARF. 2 Large rearrangement only.



SPECIMEN


PATIENT




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Presence of genetic variants of uncertain significance (VUS) that are not considered clinically significant are reported.

When new evidence about a variant is identified, updated information will be made available to the healthcare provider through an amended report.

Variants of uncertain significance (VUS) are currently not clinically actionable; the available evidence does not suggest that VUSs be used to change patient medical management.

Variants, Favor Polymorphism / Polymorphism are genetic variants for which available evidence indicates that the variant is highly unlikely to alter protein production and/or function or contribute substantially to cancer risk. Variants of this type are not reported.



6

Positive: myRisk Management Tool

© 2014, Myriad Genetic Laboratories, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 800-469-7423 FX: 801-584-3615 myRisk Management Tool: Page 1 of 5

CONFIDENTIALCONFIDENTIAL

GENE MUTATION

BRCA1 c.68_69del (p.Glu23Valfs*17)

THIS GENETIC TEST RESULT IS ASSOCIATED WITH THE FOLLOWING CANCER RISKS:

HIGH RISK: Female Breast, Ovarian

ELEVATED RISK: Pancreatic



SPECIMEN


PATIENT








FAMILY MEMBER


AGE AT DIAGNOSIS

Patient None

Mother Breast 45

Maternal Aunt Breast 55

This information was provided by a qualified healthcare provider on the test request form and was not verified by Myriad.



Patients will receive a snapshot summary of the

genetic results and the associated risk levels for

eight cancer sites.

The personal and/or family history provided is used for family history-based

risk assessment.

The symbol in the orange box indicates need

for provider attention. Information on modified management is available

on subsequent pages if appropriate.




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CONFIDENTIAL

Name: Patient Name DOB: Jan 12, 1970 Accession #: 00001144-BLD Report Date: Jun 30, 2014



CANCER RISK FOR BRCA1 CLINICALLY SIGNIFICANT MUTATION

CANCER TYPE CANCER RISK RISK FOR GENERAL POPULATION

FOR FEMALE RELATIVES

FEMALE BREAST

To age 50 Up to 51% 1.9%

To age 70 Up to 87% 7.3%

Second Breast within 5 years of First Breast 20% 2%

OVARIAN

To age 50 Up to 23% 0.2%

To age 70 Up to 44% 0.7%

Ovarian within 10 years after Breast 12.7% <1%

FOR MALE RELATIVES

MALE BREAST

To age 70 1.2% <0.1%

PROSTATE

To age 70 Up to 16% 8.2%

FOR FEMALE AND MALE RELATIVES

PANCREATIC

To age 80 Elevated Risk 1%


END OF MYRISK MANAGEMENT TOOL.


CONFIDENTIAL




OVERVIEWHereditary Breast and Ovarian Cancer Syndrome (HBOC):

• This patient has been found to have a mutation in the BRCA1 gene. Individuals with mutations in BRCA1 have a condition called Hereditary Breast and Ovarian Cancer syndrome (HBOC).

• Women with HBOC have a high risk for developing breast and ovarian cancer. There are also high risks for fallopian tube cancer and primary peritoneal cancer.

• Men with HBOC due to mutations in BRCA1 have an elevated risk for breast and prostate cancer. The increased risk for prostate cancer may be most significant at younger ages.

• Male and female patients with HBOC due to mutations in BRCA1 have an elevated risk for pancreatic cancer.

• Although there are high cancer risks for patients with HBOC, there are interventions that have been shown to be effective at reducing many of these risks. Guidelines from the National Comprehensive Cancer Network (NCCN) for the medical management of patients with HBOC are listed below. It is recommended that patients with BRCA1 mutations and a diagnosis of HBOC be managed by a multidisciplinary team with experience in the prevention and treatment of the cancers associated with HBOC.

CANCER TYPE CANCER RISKRISK FOR

GENERAL POPULATIONRELATED TO

FEMALE BREAST



Second primary within 5 years of first diagnosis 20% 2.0% BRCA1

OVARIAN



Ovarian cancer within 10 years of breast cancer diagnosis

12.7% <1% BRCA1

PANCREATIC

To age 80 Elevated Risk 1.0% BRCA1

WHAT ARE THE PATIENT’S GENE-RELATED CANCER RISKS?If more than one gene mutation increases a specific cancer risk (e.g., breast), only the highest cancer risk is shown. If this patient has more than one gene mutation, risk estimates may be different, as this analysis does not account for possible interactions between gene mutations.


CONFIDENTIAL




WHAT MANAGEMENT FOR CANCER RISKS SHOULD BE CONSIDERED?Clinical management guidelines are based on this patient’s personal and family history and genetic test results. Unless otherwise stated, management guidelines included below are limited to those issued by the National Comprehensive Cancer Network (NCCN). See the reference listed for more details. If management for a specific cancer (e.g., breast) is available due to multiple causes (e.g., a mutation and a family history, or multiple mutations in different genes), only the most aggressive management is shown. Guidelines related to the patient’s long-term care for cancer prevention are included. Guidelines for the treatment of an existing cancer are not included. Any discussion of medical management options is for general informational purposes only and does not constitute a recommendation. While genetic testing and medical society guidelines provide important and useful information, medical management decisions should be made in consultation between each patient and his or her healthcare provider.


(Unless otherwise indicated by findings)

RELATED TO

FEMALE BREAST

Breast awareness- Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness1

18 years NA BRCA1

Clinical breast exam1 25 years Every 6 to 12 months BRCA1

Mammography and Breast MRI1 25 years, or individualized based on earliest diagnosis in family

Annually BRCA1

Consider options for breast cancer chemoprevention (i.e., tamoxifen)1 Individualized NA BRCA1

Consider risk-reducing mastectomy1 Individualized NA BRCA1

OVARIAN

Consider options for ovarian cancer chemoprevention (i.e., oral contraceptives)1 Individualized NA BRCA1


35 to 40 years, after completion of childbearing, or individualized based

on the earliest diagnosis in the familyNA BRCA1


30 years, or individualized based on earliest diagnosis in the family

Every 6 months BRCA1

PANCREATIC

Currently there are no specific medical management guidelines for pancreatic cancer risk

NA NA BRCA1

1. Daly M, et al. NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. Available at http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf.


In reports with a positive result, the myRisk Management Tool blends the genetic information with family history to provide

guideline-based management considerations

Guideline-based Management Tool

Clinical management recommendations are

refer enced from the National Comprehensive Cancer Network (NCCN) as well as other specialty

and consensus groups.

Providers may indicate other personalized

management considerations as needed

Information for family

Gene-related overview and cancer risk

Personal cancers are not assessed for risk and management considerations. The medical management considerations provided are only meant to be a broad overview, and are provided for informational purposes. Actual care of the patient is the responsibility of the treating physician and should be based on careful review of all patient factors, and consideration of the cited references and other resources.



8

Negative: myRisk Management Tool


CONFIDENTIAL







No clinically significant mutations were identified in this patient. However, based on personal/family history, the patient’s cancer risks may still be increased over the general population. Clinical management should be based upon personal and family history.

FAMILY MEMBER


AGE AT DIAGNOSIS

Patient None

Father Prostate 42

Paternal Aunt Breast 31

Maternal Aunt Endometrial 49

This information was provided by a qualified healthcare provider on the test request form and was not verified by Myriad.


myRisk Management ToolRECEIVING HEALTHCARE PROVIDER


SPECIMEN


PATIENT


Patients will receive a snapshot summary of the

genetic results and the associated risk levels for

eight cancer sites.

The personal and/or family history provided is used for family history-based

risk assessment.

The symbol in the orange box indicates need

for provider attention. Information on modified management is available

on subsequent pages if appropriate.




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CONFIDENTIAL




WHAT MANAGEMENT FOR CANCER RISKS SHOULD BE CONSIDERED?Clinical management guidelines are based on this patient’s personal and family history and genetic test results. Unless otherwise stated, management guidelines included below are limited to those issued by the National Comprehensive Cancer Network (NCCN). See the reference listed for more details. If management for a specific cancer (e.g., breast) is available due to multiple causes (e.g., a mutation and a family history, or multiple mutations in different genes), only the most aggressive management is shown. Guidelines related to the patient’s long-term care for cancer prevention are included. Guidelines for the treatment of an existing cancer are not included. Any discussion of medical management options is for general informational purposes only and does not constitute a recommendation. While genetic testing and medical society guidelines provide important and useful information, medical management decisions should be made in consultation between each patient and his or her healthcare provider.



(Unless otherwise indicated by findings)

RELATED TO

FEMALE BREAST

Breast Awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness1

Individualized NAFamily History

(>20% lifetime risk)

Clinical breast exam1,2 30 yearsEvery 6 to 12

monthsFamily History


Consider breast MRI in addition to mammography1,2 30 years AnnuallyFamily History


Consider risk reduction strategies1,2 Individualized NAFamily History


OTHER CONSIDERATIONS

One or more Variants of Uncertain Significance (VUS) were identifed (see myRisk Genetic Result). Recommend clinical management based on personal / family history and other risk factors.

Individualized NA Uncertain Variant(s)

1. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3.

Available at http://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf.

2. Claus EB, et al. Autosomal dominant inheritance of early-onset breast cancer. Implications for risk prediction. Cancer. 1994 73:643-51. PMID: 8299086.

The myRisk Management Tool also helps raise awareness of additional management considerations for patients with negative results

Management considerations for familial

risk are assessed for patients with positive as well as negative results. Guidelines and criteria

used include: NCCN, CAPS, the Claus Risk

Model (>20% lifetime breast cancer risk),

Amsterdam Criteria, and others.

When one or more VUSs are identified, clinical

management is based on personal/family history

and other risk factors.

Guideline-based Management Tool

Personal cancers are not assessed for risk and management considerations. The medical management considerations provided are only meant to be a broad overview, and are provided for informational purposes. Actual care of the patient is the responsibility of the treating physician and should be based on careful review of all patient factors, and consideration of the cited references and other resources.



of more than 30 scientists who determine the clinical sig-nificance of variants. By tapping the expertise of these indi-viduals from all applicable disciplines, myVision represents unrivaled experience and expertise in variant classification.

Myriad’s Variant Classification Program

Myriad’s commitment to provide the most accurate testing doesn’t stop when your patient’s results are in your hands. We understand that Myriad’s results influence the clinical path you take with your patient. That’s why myVision is part of Myriad’s commitment to patients and their families that lasts a lifetime.

• When deemed clinically significant for the patient’s results, Myriad will reach out to offer targeted genetic testing at no cost to selected family members in order to gather more information about a VUS result to assist in the reclassification process

• When an uncertain variant result is reclassified, an amended report is made available to the provider

• Myriad continues to evaluate additional information as it emerges in order to classify and reclassify variants quickly and accurately

Experience you depend on. Results you can trust.

myVision™ Myriad Variant Classification Program

No company has more experience in genetic testing for hereditary cancer than Myriad. Myriad has delivered more than one million test results—which means the myVision program is based on the largest and most robust database in the industry to identify, classify, and assign clinical signifi-cance to genetic variants. Myriad is committed to translating the experience in result analysis and interpretation of vari-ants to reduce variants of uncertain significance (VUS) in all genes on the myRisk™ panel and ensure:

• Accurate, clinically actionable results from every Myriad test performed

• Reduced uncertainty for patients and families

• Confidence for providers counseling their patients

Myriad has pioneered the field of variant classification. Through the development of powerful scientific techniques and statistical reclassification methods, Myriad has created the most advanced variant classification program in the industry.

Classification by industry-leading experts

Every day, new variants are evaluated and classified by the Myriad Variant Classification Program, led by a diverse team

*ABGC=American Board of Genetic Counseling.†ABMG=American Board of Medical Genetics.

‡ Eggington JM, Bowles K, Moyes K, Manley S, Esterling L, Sizemore S, Rosenthal E, Theisen A, Saam J, Arnell C, Pruss D, Bennett J, Burbidge LA, Roa B and Wenstrup RJ (2013). A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clinical Genetics. DOI: 10.1111/cge.12315

HEAD L AB DIRECTOR CHIEF MEDICAL OFFICER

ABGC*-CERTIFIED GENETIC COUNSELORSSTATISTICIANSRESEARCH SCIENTIST

MOLECUL AR BIOLOGISTSVARIANT SPECIALISTSABMG*-CERTIFIED L ABOR ATORY DIRECTORS

INFORMATICS SPECIALISTSBIOCHEMISTSSTRUCTUR AL BIOLOGISTS

Variant classification: the initial process through which all available data on a variant are analyzed and a clinical interpretation is assigned

Variant reclassification: a change in classification based on new information or knowledge

Variant of uncertain significance:

A genetic change where the association with a hereditary cancer (if any) is not yet known



* Large rearrangement testing.

Pheno® — A family history weighting algorithm—This tool, unique to Myriad, compares the severity of family histories of patients who carry a specific variant to that of families who carry known deleterious mutations and to families in whom no mutation was detected.

M-Co™ (Mutation Co-occurrence) — This statistical model is unique to Myriad and is used to discover benign variants, which leverages the rarity of multiple deleterious mutations co-occurring in a single patient.

Literature evaluation — Myriad’s scientists and statisticians continually evaluate the published literature, a process that often includes a reanalysis of experimental data to deter-mine whether data is clinically actionable.

60%

40%

Techniques using data unique to Myriad • Pheno® analysis • M-Co™ analysis

Techniques enhanced by Myriad • Literature evaluation • Evolutionary conservation • Segregation analysis • In trans co-occurrence • Population frequency • Protein structural analysis • In-silico splicing analysis

Evolutionary conservation — This method compares protein sequences across many species to determine the classifica-tion. Due to the high false-positive rate of this method, Myr-iad uses it very conservatively, for downgrading of variants only.

Segregation analysis — The classic gold-standard approach to variant classification where variants are tracked in families to determine if they are associated with cancer.

In trans co-occurrence — For some genes, deleterious muta-tions on both copies of the gene can cause well-defined and easily distinguishable diseases. Thus, variants co-occurring with known deleterious mutations on opposing gene copies in patients without the relevant disease are more likely to be benign.

Population frequency — This method compares the fre-quency of variants in control populations to those seen in affected populations tested at Myriad to determine if vari-ants are associated with cancer.

Protein structural analysis — This method uses advanced structural biology techniques to identify variants that will severely disrupt protein function leading to cancer formation.

In-silico splicing analysis — While it is standard laboratory procedure to evaluate novel variants for potential RNA splic-ing effects using publicly available in-silico methods, Myriad also uses a proprietary in-silico tool for this evaluation.

Cutting-edge variant classification techniques‡

myVision™ employs a number of classification techniques, some of which have been used by geneticists for many years. Myriad also uses a number of novel, proprietary techniques made possible by Myriad’s ability to test many patients. We are continually working towards creating and perfecting new methodologies to help classify variants.

VUS Rate by Gene

GeneYear Testing

StartedMyriad’s 2013

VUS rate

BRCA1 1996 0.6%

BRCA2 1996 1.6%

MLH1 2000 1.5%

MSH2 2000 1.9%

MSH6 2005 3.0%

PMS2 2011 2.6%

EPCAM* 2011 0.01%

Decline in Rate of BRCA1/2Variants of Uncertain Significance

15%

12%

9%

6%

3%

0%2002 2006 2008 2013

The proof is in Myriad’s ability to rapidly decrease VUS rates

The myVision™ Variant Classification Program has dramatically reduced the VUS rate for Myriad’s genetic tests, which allows the company to provide you with the most accurate, clinically actionable results for your patients.



Description of Analysis:The myRisk™ Hereditary Cancer test includes germline DNA-based next generation sequencing analysis (NGS) of a panel of genes related to Hereditary Cancer. Large rearrangement testing for dele-tions and duplications is performed by microarray-CGH analysis, with noted exceptions. NGS analysis of the coding region is performed for the following genes: APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p16INK4a and p14ARF), CHEK2, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11, TP53. For the EPCAM gene, only large rearrangement analysis is performed (EPCAM deletions that affect adjacent MSH2 gene expression are associated with Lynch syndrome). Portions of non-coding intronic regions are also analyzed by sequencing analy-sis and typically do not extend more than 20 base pairs (bp) proxi-mal to the 5’ end and 10 bp distal to the 3’ end of each exon.

Description of Method:Patient samples are assigned a unique bar-code for robotic-assisted continuous sample tracking. Genomic DNA is extracted and purified from peripheral blood samples or buccal mouthwash samples sub-mitted for molecular testing.

DNA sequence analysis by NGS: The samples are prepared through a PCR-based target-enrichment strategy for subsequent next-gen-eration sequencing. Aliquots of patient genomic DNA are sonicated. The fragmented DNA is dispersed in oil into picoliter-sized aque-ous droplets that are merged with a dropletized Target Enrichment Primer Library. The resulting emulsion of microdroplets is subjected to PCR amplification. Emulsion PCR products are purified and sub-jected to secondary PCR to incorporate sequencing adaptors for NGS and indexing barcodes for individual sample tracking. Barcoded samples from up to 96 patients are pooled and loaded onto massive-ly-parallel NextGen sequencers for 2 x 150 base paired-end reads. Primer design was optimized for NGS analysis of genes with known pseudogene regions. Supplementary workflows were developed to analyze the PMS2 and CHEK2 genes as described below.

Supplementary sample preparation and NGS of PMS2 and CHEK2: Long Range (LoRa) PCR is used for initial amplification of PMS2 and CHEK2 gene regions to avoid well-characterized pseudogenes. Aliquots of patient DNA are subjected to gene-specific LoRa ampli-fication of: 1) PMS2 exons 1-5; 2) PMS2 exon 9; 3) PMS2 exons 11-15; 4) CHEK2 exons 11-15. The four separate LoRa amplicons are diluted and subjected to secondary PCR to incorporate sequencing adap-tors for NGS and indexing barcodes for individual sample tracking. The barcoded samples are pooled and loaded onto massively-paral-lel NextGen sequencers for 2 x 150 base paired-end reads.

NGS Data Analysis and ConfirmationA combination of commercial and laboratory-developed software is used for NGS data processing, which includes base-calling, align-ment, variant identification, annotation, and quality metrics. Genetic variants are reviewed by computer software and human reviewers. The minimum depth of coverage used for sequence determination by NGS is 50x per base. All clinically significant variants identi-fied by NGS and regions that do not meet NGS quality metrics are independently confirmed with orthogonal site-specific Sanger sequencing.

Large Rearrangement AnalysisGenomic DNA from patients is analyzed by microarray-CGH analysis to determine copy number abnormalities indicative of deletion or duplication mutations. Microarray probe design was optimized to avoid known pseudogene regions, which includes the use of flank-ing intron probes in certain genes. For the PMS2 and CHEK2 genes

Myriad myRisk™ Hereditary Cancer Technical SpecificationsEffective: Aug 1, 2014 // Myriad Genetic Laboratories

TEST RESULTS SHOULD BE USED ONLY AFTER REVIEW OF THE FOLLOWING SPECIFICATIONS:

specifically, large rearrangements are evaluated with a Multiplex Ligation-dependent Probe Amplification (MLPA) assay instead of microarray-CGH. For microarray-CGH analysis, approximately 9,600 probes interrogate coding exons and limited flanking intron regions of tested genes. Additionally, certain functionally characterized pro-moter elements are also covered on microarray-CGH (APC, BMPR1A, BRCA1, BRCA2, MLH1, MSH2, MSH6, PTEN, SMAD4, STK11 and TP53). Probe signals are analyzed using laboratory developed software that compares the ratio of bound patient DNA to that of a differentially labeled reference DNA to identify regions of altered copy number. Patient samples positive for deletions or duplications are confirmed by repeat microarray-CGH analysis and / or MLPA.

Single Site Analysis DNA sequence or large rearrangement analysis is performed for a specified variant in APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p16INK4a and p14ARF), CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, SMAD4, STK11 and TP53. Single site testing for sequencing mutations is performed using Sanger sequencing. When the single site mutation is a deletion or duplication mutation, microarray comparative genomic hybridization analysis is used for all genes except PMS2 and CHEK2, for which large rearrangements are assessed with MLPA. In some cases, long-range PCR analysis and/or sequencing of the resulting PCR product is used to detect specific, previously reported insertions.

Performance Characteristics:Analytical specificity: The incidence of a false report of a genetic variant or mutation resulting from technical error is considered neg-ligible because of independent confirmation of all clinically signifi-cant genetic variants (see above). The incidence of a false report of a clinically significant genetic variant or mutation resulting from errors in specimen handling and tracking is estimated from validation stud-ies to be less than one percent (<1%).

Analytical sensitivity: Failure to detect a genetic variant or muta-tion in the analyzed DNA regions may result from errors in specimen handling and tracking, amplification and sequencing reactions, or computer-assisted analysis and data review. The rate of such errors is estimated from validation studies to be less than one percent (<1%). The analytical sensitivity of next-generation sequencing for genes in the myRisk test is estimated to be >99.92% (lower bound of 0.95 C.I.), based on complete concordance in a comparative study of NGS and Sanger sequencing performed on 100 individual ano-nymized DNA samples with 3,923 identified sequence variants. NGS and Sanger sequencing comparisons for BRCA1 and BRCA2 on an additional 1,864 anonymized DNA samples estimates an analytical sensitivity of >99.96% (lower bound of 0.95 C.I.) for NGS analysis of the BRCA1 and BRCA2 genes within the myRisk test. Validation studies for the large rearrangement component of the assay com-prised 212 samples for microarray-CGH analysis of 23 genes in the myRisk panel, including 51 genomic positive controls with charac-terized large rearrangement mutations. Validation studies were also performed for MLPA of 110 samples for PMS2 and CHEK2, including 5 genomic positive controls with characterized large rearrangement mutations. Synthetically generated positive controls were used when genomic positive control samples were not available. All results for large rearrangements were 100% concordant.

Test reproducibility: Analytical validation studies included a repro-ducibility study comprising 4 individual anonymized DNA samples collectively carrying 199 sequence variants which were confirmed by Sanger sequencing. Each of these 4 samples was sequenced by NGS in triplicate across three batches (i.e., 4 samples x 9 replicates each) which demonstrated 100% reproducibility.



Limitations of method: Unequal allele amplification may result from rare polymorphisms under primer sites. The presence of pseudogenes may complicate the detection of rare sequencing and large rearrangement mutations in certain genes. There may be uncommon genetic abnormalities such as specific insertions, inver-sions, and certain regulatory mutations that will not be detected by myRisk. This analysis, however, is believed to rule out the majority of abnormalities in the genes analyzed. Genetic testing results on blood or buccal samples may not reflect the germline genetic status of patients with a hematologic malignancy, or patients who under-went allogeneic bone marrow transplants. In such cases, please contact Medical Services to discuss re-submission of an appropriate sample type.

Description of Nomenclature:All mutations and genetic variants are referenced to cDNA positions on their respective primary transcripts and named according to the HGVS convention (J Mol Diagn. 2007 Feb;9(1):1-6). Transcript IDs are indicated on patient reports with their associated variants (Table 1).

Interpretive Criteria:Functional Variant InterpretationsA functional interpretation is assigned to each variant identified. This interpretation reflects whether or not the variant is predicted to result in a significant change to normal protein production and/or function. It may not necessarily reflect cancer risk (see Clinical Variant Interpretations).

“Deleterious mutation”: Includes most nonsense and frameshift mutations that occur at/or before the last known deleterious amino acid position of the affected gene. In addition, specific missense mutations and non-coding intervening sequence (IVS) mutations are recognized as deleterious on the basis of data derived from linkage analysis of high risk families, functional assays, biochemical evidence, statistical evidence, and/or demonstration of abnormal mRNA transcript processing.

“Genetic variant, suspected deleterious”: Includes genetic variants for which the available evidence indicates a high likelihood, but not proof, that the mutation is deleterious. The specific evidence sup-porting an interpretation will be summarized for individual variants on each such myRisk Genetic Result.

“Genetic variant of uncertain significance”: Includes missense variants and variants that occur in analyzed intronic regions whose functional significance has not yet been determined, as well as non-sense and frameshift mutations that occur distal to the last known deleterious amino acid positions of the affected genes.

“Genetic variant, favor polymorphism” and “Genetic variant, poly-morphism”: Includes genetic variants for which available evidence indicates that the variant is highly unlikely to alter protein production and/or function or contribute substantially to cancer risk. Variants of this type are not reported.

Clinical Variant InterpretationsA clinical interpretation is assigned to each variant identified. This interpretation reflects whether or not the variant is predicted to be associated with significantly increased risk for one or more cancer types.

“High Cancer Risk”: Includes genetic variants for which absolute cancer risk is predicted to be higher than ~5% with a ~3-fold or higher increased relative risk over that of the general population. Strong data is available to support gene-specific risk estimates, although actual variant-specific risks may differ.

“Elevated Cancer Risk”: Includes genetic variants for which there is sufficient data to indicate that the specific variant increases risk for one or more cancers over that of the general population. These risks may be lower than those conveyed by “High Cancer Risk” variants or may be supported by less solid, but still significant, data.

“Clinical Significance Unknown”: Includes genetic variants for which there is insufficient data to determine whether or not the variant is associated with increased cancer risk.

“Clinically Insignificant”: Includes genetic variants for which available evidence indicates that the variant is highly unlikely to significantly contribute to cancer risk. Variants of this type are not reported.

“Cancer Risk May Be Increased”: Includes genetic variants for which there is limited evidence that the variant may be associated with increased cancer risk. However, this evidence may be insufficient to support modifications to clinical intervention. Evidence utilized will be indicated on the myRisk Genetic Result.

“Special Interpretation”: Includes genetic variants with more com-plex clinical interpretations. Specific interpretations will be provided for each variant on the myRisk Genetic Result.

Summary Interpretations“Clinically significant mutation identified”: Includes myRisk Genetic Results in which one or more genetic variants, which are associated with the potential to alter medical intervention, were identified.”

“No clinically significant mutation identified”: Includes myRisk Genetic Results in which either no genetic variants were identified or all identified variants were classified as “Clinical Significance Unknown” or “Clinically Insignificant.”

Change of interpretation and issuance of amended reportsThe classification and interpretation of all variants identified in the assay reflects the current state of scientific understanding at the time the report is issued. In some instances, the classification and inter-pretation of such variants may change as new scientific information becomes available. Whenever changes in variant interpretation have the potential to alter clinical intervention, an amended report will automatically be provided by Myriad Genetic Laboratories.

Table 1: Transcript IDs associated with myRisk genes

Gene Name Transcript ID

APC NM_000038.5

ATM NM_000051.3

BARD1 NM_000465.3

BMPR1A NM_004329.2

BRCA1 NM_007294.3

BRCA2 NM_000059.3

BRIP1 NM_032043.2

CDH1 NM_004360.3

CDK4 NM_000075.3

CHEK2 NM_007194.3

EPCAM NM_002354.2

MLH1 NM_000249.3

MSH2 NM_000251.2

MSH6 NM_000179.2

MUTYH (alpha5)MUTYH (alpha3)

NM_001128425.1NM_001048171.1

NBN NM_002485.4

P14ARF NM_058195.3

P16 NM_000077.4

PALB2 NM_024675.3

PMS2 NM_000535.5

PTEN NM_000314.4

RAD51C NM_058216.2

RAD51D NM_002878.3

SMAD4 NM_005359.5

STK11 NM_000455.4

TP53 NM_000546.5

http://www.ncbi.nlm.nih.gov/refseq/



Laboratory Process

VariantReclassification

Customer Service Case Processing

Report Generation / Quality Assurance Lab Director Approval

DNA Extraction Targeted Gene Analysis

The testing platform for Myriad myRisk™ is Next Genera-tion Sequencing (NGS), a high throughput technology that allows rapid sequencing of large stretches of DNA base pairs. Unlike any other NGS platform, Myriad fine-tunes the degrees of resolution, or ‘coverage,’ which generally refers to the average number of sequencing reads that align to each base within the sample DNA.

To maintain the highest quality, Myriad does not report any finding with less than 50x coverage on NGS alone, with our average depth of coverage being >1,500x. Sanger sequenc-ing, the long-time gold standard of gene sequencing, is used to refine or confirm findings when appropriate.

Other methods, including multiplex PCR, long-range PCR, gene-specific MLPA and targeted microarray-CGH, are used in conjunction with NGS. These additional methods provide

support in finding difficult-to-detect large rearrangements and overcoming the obstacle of pseudogenes.

While NGS is a widely used method, Myriad has put signif-icant effort in optimizing the materials that are generally available to make for a superior test when compared to “off-the-shelf” materials. Our vast experience has allowed us to optimize primer and library design to increase the sensitivity and specificity of the Myriad myRisk test.

This serves as only one part of many steps that Myriad pursues to ensure the highest quality and sensitivity for every sample that is submitted. The following cycle shows the extensive laboratory process from DNA extraction and sequencing to laboratory director approved reports that occur in 21 days or less, on average.

• Medical review of result and family history

• Quality checks on laboratory data and patient demographic entries

• Confirmation of data, quality, and result output

• Cutting edge reclassification techniques

• Overnight result delivery

• Chain of custody - Barcode assisted

sample tracking - Accessioning through

reporting

• Free Myriad myRisk test kit

• Double data entry• Insurance pre-verification• Test release to lab

Sample Submission

Provider

powered by:

*If clinically significant mutation or unusual case identified

1

Data Review

• Proprietary data review software algorithm: validated for maximum sensitivity and specificity

• Three independent data review experts to assess results

4

7 9

VariantClassification

• ANY variant detected is tracked and evaluated

• Daily meetings take place to classify variants

5

2 3

ConfirmatoryTesting*

• Appropriate cases reviewed by Myriad’s unusual case committee for additional studies in boutique lab

UnusualCase

Pathway

6

8

• NGS Sequencing: optimized primer library to increase sensitivity and specificity with minimum 50x and average >1500x depth of coverage

• Targeted Microarray: custom high-density probe designs to optimize large rearrangement analysis

• MLPA: assay optimized for pseudogene regions

• Sanger sequencing: used to refine or confirm findings when appropriate.



1 Q: What are Myriad myRisk™ minimum depth of cover-age requirements and average coverage overall?

A: We would not report any finding with less than 50x cov-erage for NGS without Sanger confirmation. We observe an average depth of coverage of greater than 1,500x.

While there are no coverage recommendations for clin-ical NGS use, we set our coverage by determining risk of missing a sequencing mutation at various coverage levels. These depth cut-offs were then validated by the labora-tory. Regions with coverage less than Myriad’s thresholds are Sanger sequenced to ensure optimal sensitivity and specificity.

__________________________________________________

2 Q: How are gaps in sequencing handled with Myriad myRisk and are they reported?

A: Our customized library has been designed to provide suf-ficient depth of coverage for all sequenced regions. However, regions with lower coverage can arise with NGS sequencing and are not acceptable for clinical results. When gaps in our minimum required NGS coverage do occur, we analyze that region with Sanger sequencing so as not to miss clinically significant mutations. Patient tests will not be reported with-out complete high quality analysis of all panel genes.

__________________________________________________

3 Q: When a finding occurs with NGS, how is it confirmed?

A: All deleterious and suspected deleterious variants are subsequently confirmed by Sanger sequencing prior to reporting. However, based on complete concordance in a comparative study of Myriad’s myRisk and Sanger sequenc-ing performed on 3,923 variants (including VUS and vari-ants, favor polymorphism), it is validated that false positives of any variants detected through myRisk is negligible.

__________________________________________________

4 Q: How do you know that Myriad myRisk NGS plat-form is as sensitive as current BRACAnalysis®?

A: An internal validation study looked at 1,824 anonymized samples that had previously undergone Sanger sequencing analysis of BRCA1 and BRCA2. Sanger sequencing identi-fied 15,878 variants. Our Myriad myRisk NGS platform then identified 15,877 variants at an initial analytical sensitivity of >99.96% (Lower bound 95% C.I.) for NGS sequencing of BRCA1 and BRCA2. One polymorphic variant was missed due to that patient having a variant under the NGS primer

for that particular sequencing reaction (this risk is inherent to PCR and may occur with both Sanger sequencing tech-nology as well as NGS). Process controls are in place to min-imize the rare occurrence of variants under the primer sites. Data has been published at ASHG.

__________________________________________________

5 Q: What are the size of insertions and deletions (indels) that Myriad myRisk will detect?

A: Myriad myRisk has been designed to detect both small insertions and deletions and larger gene rearrangements. Deletions and duplications that affect one or more exons are detectable by targeted microarray-CGH or MLPA analysis. Small deletions or duplications contained within an exon are detectable by NGS.

__________________________________________________

6 Q: How were the genes included in the Myriad myRisk test determined?

A: We focused on including genetic mutations for which there is established data showing clinical significance. Our goal is to have a meaningful, clinically-actionable panel of hereditary cancer genes. Genes for which there is unclear clinical guidance were not included to ensure maximum clin-ical utility of test results.

__________________________________________________

7 Q: How will variants be reported for Myriad myRisk?

A: Results will focus on clinically significant mutations and family history information. There will be a clear positive or negative result indicated. Positive results include deleterious or suspected deleterious mutations. Negative results lack a clinically significant deleterious or suspected deleterious mutation and will focus on management recommendations based on personal and/or family cancer history.

Variants of Uncertain Significance (VUS) will be reported on the myRisk Genetic Result as non-clinically significant findings based on current state of scientific understanding. Polymorphisms and favor polymorphisms are not included on the report as these types of variants are considered clin-ically benign.

Technology FAQ

PRIMEREXON

EXONPRIMER

Myriad’s Targeted Microarray

Deletion missed through technology used at other labs

Deletion detected through Myriad’s targeted microarray

Lab X’s Technology



8 Q: Which promoter regions are evaluated using the NGS panel and how many bases into introns will be

sequenced?

A: We are generally not sequencing more than 20 nucleo-tides upstream of the start codon as variants in the 5’UTR are difficult to interpret and thus not clinically significant. We sequence -20 nucleotides into the introns prior to each exon and +10 nucleotides after each exon.

__________________________________________________

9 Q: Which genes in Myriad myRisk™ have pseudogenes and how do you analyze them?

A: The PMS2 and CHEK2 genes have known homologous pseudogenes, which complicate genetic analyses for certain analyzed regions. The detection of sequencing mutations uti-lizes long range PCR to amplify certain coding gene-specific regions prior to NGS analysis. For large rearrangement muta-tions MLPA analysis is utilized. Probes on MLPA are designed to distinguish the coding genes from the pseudogenes. Assay performance for other pseudogene-containing genes such as PTEN is optimized by careful design of NGS primers for sequence analysis, and microarray probes for deletion/duplication analysis.

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10 Q: How do you determine the classification of vari-ants that have not been reported previously?

A: Each new variant discovered is evaluated and classified by a team of scientists and genetic counselors at Myriad. This diverse team of over 30 scientists meets regularly to determine the clinical significance of these variants. Multi-ple proprietary methods are used to interpret variants. Visit www.MyriadPro.com/myVision to learn more.

11 Q: Is ongoing reclassification of variants done with Myriad myRisk variants of uncertain significance?

A: Yes - More than 15 years of high-volume testing at Myriad has resulted in thousands of variant reclassifications and that same lifetime commitment will be made for all of the genes in Myriad myRisk. Myriad is committed to provide clinically actionable test results for all patients. Over time, as we study these variants and learn more, we will reclassify many variants and we will send amended reports proactively to healthcare providers.

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12 Q: Will Myriad confirm variants found at other laboratories?

A: The interpretation of laboratory results is an integral part of the clinical testing service and as such, is regulated by CLIA as a Laboratory Developed Test and by the FDA as a medical device. Myriad’s commitment to the highest quality for mutation and variant interpretations begin as early as the initial testing analysis. To ensure we minimize all uncer-tainties associated with variable testing or reimbursement processes outside of Myriad, we do not routinely provide classification information for mutations identified in other laboratories.

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13 Q: If a sample fails to be analyzed by routine NGS or other methods, or has an unusual finding, what is

done with that sample?

A: While the vast majority of patient samples produce results within the expected range, rare samples may produce unexpected results or results requiring additional analyses for correct interpretation. Myriad is dedicated to provide patients and providers with accurate and informative test results. To this end, we have a dedicated team composed of scientists spanning multiple areas of scientific and clinical expertise to perform additional analyses of these samples. These analyses are sample-specific and are determined on a case-by-case basis.

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14 Q: Will Myriad continue to offer current test offer-ings (BRACAnalysis®, MultiSite 3, Single Site analy-

sis, COLARIS®, etc.)?

A: All current test offerings will remain available for the fore-seeable future. Current test offerings will be run using their current technologies.

For information on analytical sensitivity and specificity please refer to Myriad myRisk technical specifications at:

www.MyriadPro.com/myRisk

Myriad’s Approach

Lab X’s Approach

+10 -20

1 2

+5 -5

1 2



Myriad Provides Quality Support for Providers & Patients

• Billing assistance

• Customer service

• MySupport360®

• Financial support

• Genetic counselors

• Lifetime clinical support

• Field genetic experts

• Specialized sales force

• Protocol/process experts

• Ongoing genetics education

• Updated reports

• Quality results

• Gold standard variant classification

• Most appropriate patients pay $0

• Broad insurance coverage

• 97% of private insurance companies have coverage for Myriad’s hereditary cancer testing

PATIENT SUPPORT

PROVIDER SUPPORT

FINANCIAL SUPPORT

www.MyriadPro.com

www.MyriadPromise.com

www.MySupport360.com



www.MyriadPro.com

Myriad Genetic Laboratories, Inc.

320 Wakara Way

Salt Lake City, UT 84108

CONTACT MYRIAD’S CUSTOMER SERVICE

Tel: (800) 469-7423

Fax: (801) 584-3615

Email: [email protected]

For the most up-to-date clinical information please visit www.MyriadPro.com/myRisk. The format and contents of this guide are proprietary and may not be copied or used without permission from Myriad. Myriad, the Myriad logo, myRisk and the myRisk logo, MyriadPro, the MyriadPro logo, Myriad Promise, the Myriad Promise logo, myVision, the myVision logo, MySupport360, the MySupport360 logo, Pheno and MCo are either trademarks or registered trademarks of Myriad Genetics, Inc. in the United States and other jurisdictions. ©2014, Myriad Genetic Laboratories, Inc. // MRHCCH/Updated 06/19/2014

Documents

MyRisk Clinical Handbook - SciencewerkeDX