Hereditary Breast & Gynecologic Cancer Genetic Testing

A Comprehensive Guide

1 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

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Hereditary Breast and Gynecologic Cancer

Breast Cancer Breast cancer is the most common cancer found in women and approximately 1 out of every 8 (12%)1 women will be diagnosed with breast cancer in her lifetime. Although the disease occurs more frequently in women, breast cancer can also occur in men.

Gynecologic Cancer Endometrial and ovarian cancers are the two gynecologic cancers most often associated with hereditary cancer syndromes. Endometrial cancer is the most common cancer found in the female reproductive system and approximately 1 out of every 36 (2.8%)1 women will be diagnosed with endometrial cancer in her lifetime. Ovarian cancer is the ninth most common cancer among females and approximately 1 out of every 70 (1.4%) 1 women will be diagnosed with ovarian cancer in her lifetime.

Breast and gynecologic cancers occur when normal cells begin to grow uncontrollably, forming a malignant tumor. While the majority of breast and gynecologic cancer is sporadic and occurs by chance, approximately 5-10% of breast and endometrial cancers, and up to 25% of ovarian cancers, are hereditary. Hereditary cancers occur because an individual was born with a harmful change in a gene that increased his or her risk to develop cancer. These harmful changes are also known as pathogenic variants and can be identified through genetic testing.

The most common cause of hereditary breast and ovarian cancer are pathogenic variants in the BRCA1 and BRCA2 genes. Pathogenic variants in these genes are associated with a significant lifetime risk to develop breast, ovarian, and pancreatic cancer, among others.2 Endometrial cancer has also been reported in women with pathogenic variants in these genes. Pathogenic variants in the BRCA1 and BRCA2 genes occur in all ethnic groups however approximately 1 in 40 individuals with Ashkenazi Jewish ancestry carry one of three founder (common) variants. There are also other genes associated with hereditary breast and ovarian cancer for which testing is available.3

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The most common cause of hereditary endometrial cancer is Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer syndrome). Lynch syndrome is primarily associated with an increased risk for endometrial and colorectal cancer; however it is also associated with ovarian, stomach, pancreatic and kidney cancers, among others.2 In some cases, there are screening tests that may be performed on endometrial and colorectal tumors to help identify those at risk for Lynch syndrome. These screening tests are known as microsatellite instability (MSI) and/or immunohistochemistry (IHC) and may assist in identifying those who would benefit from genetic testing. There are also other genes associated with hereditary endometrial cancer for which testing is available.3

Genes and Lifetime RisksMany genes have been associated with an increased risk of breast and gynecologic cancer. These genes can be categorized into three main groups: High-Risk, Moderate-Risk, and Newer-Risk.

High-Risk GenesHigh-risk genes are well-studied, and pathogenic variants in these genes are associated with a significantly increased risk (greater than 4-fold risk when compared with the general population) to develop one or more cancers. These genes are often associated with well-defined hereditary cancer syndromes, which generally have published guidelines for screening and prevention. Patients with pathogenic variants in these genes may develop cancer and/or tumors at young ages or may have an increased risk for multiple cancer diagnoses in a lifetime.

High-risk genes associated with an increased risk of breast, ovarian and endometrial cancer include BRCA1, BRCA2 (BRCA-Related Breast and/or Ovarian Cancer syndrome); CDH1 (Hereditary Diffuse Gastric Cancer syndrome); EPCAM, MLH1, MSH2, MSH6, PMS2 (Lynch syndrome); biallelic pathogenic variants in MUTYH (MUTYH-Associated Polyposis or MAP); NF1 (Neurofibromatosis type 1 or NF1); PALB2; PTEN (PTEN Hamartoma Tumor syndrome, including Cowden syndrome); and TP53 (Li-Fraumeni syndrome). Figure 1 provides the lifetime risk of breast, ovarian and endometrial cancers when a pathogenic variant is identified in these high-risk genes.

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3 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Indicates Lifetime Breast Cancer Risk in General Population Indicates Lifetime Ovarian Cancer Risk in General Population Indicates Lifetime Endometrial Cancer Risk in General Population Indicates Lifetime Risk Associated with a Pathogenic Variant(s)

BRCA1

MUTYH

NF1

EPCAM, MLH1, MSH2, MSH6, PMS2

39-59%39-59%

Up to 24%

100 20 30 40 50 60 70 80 90 100

55-87%*55-87%*

CDH1 23-68%

TP53 85%

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Cancer Risk(%)

* BRCA1, BRCA2, and PALB2 pathogenic variants are also associated with an increased risk for male breast cancer.

** Lifetime risks of cancer are known to be significantly increased above the general population risk although a precise lifetime risk is unknown.

PTEN25-85%

5-28%

12-71%

BRCA2 11-27%33-84%

Increased**

Increased**

Increased**

Increased**PALB2

up to 58%*

Increased**

Figure 1: Lifetime Risk of Breast, Ovarian, and Endometrial Cancers Associated with Pathogenic Variants in High-Risk Genes

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Moderate-Risk GenesModerate-risk genes are often well-studied, and pathogenic variants in these genes are associated with a more modest risk (approximately a 2- to 4-fold risk when compared with the general population) to develop one or more cancers and/or tumors. Generally, there are limited guidelines for screening and surveillance. Similar to high-risk genes, patients with pathogenic variants in these genes may develop cancer and/or tumors at an early age and may develop multiple cancer diagnoses in a lifetime.

Newer-Risk GenesIn addition to high-risk and moderate-risk genes, other genes have been identified that are not as well-studied. Often the association with cancer and/or tumors may be newly discovered, or there may be limited data on the degree of cancer risk and/or full spectrum of tumors associated with genetic variants in these genes. Guidelines for screening and prevention are limited or not available.

Table 1 reviews the genes associated with an increased risk of breast, ovarian and/or endometrial cancers in the presence of a pathogenic variant and provides information on other cancers and/or tumors associated with these genes. Specific lifetime risk estimates are provided when available and are based on published medical literature.

5 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Gene Lifetime Cancer and/or Tumor Risks*

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BRCA1Female breast (55-87%), Ovarian (39-59%), Prostate, Male breast, Pancreatic, Fallopian tube, Primary peritoneal, Endometrial

BRCA2Female breast (32.6-84%), Prostate (up to 34%), Ovarian (11-27%), Pancreatic (5-7%), Male breast (4-7.1%), Melanoma, Fallopian tube, Primary peritoneal, Endometrial

CDH1 Gastric (44-80%), Female breast (23-68%), Colorectal

EPCAM**Colorectal (69-75%), Endometrial (12-55%), Ovarian, Gastric, Pancreatic, Biliary tract, Urinary tract, Small bowel, Brain, Sebaceous tumors, Prostate

MLH1Colorectal (22-80%), Endometrial (31-54%), Ovarian (13-20%), Gastric (6-20%), Urinary tract (1-3%), Pancreatic, Biliary tract, Small bowel, Brain, Sebaceous tumors, Prostate

MSH2Colorectal (22-80%), Endometrial (31-61%), Ovarian (10-24%), Urinary tract (8-20%), Gastric (<1-9%), Pancreatic, Biliary tract, Small bowel, Brain, Sebaceous tumors, Prostate

MSH6**Colorectal (20-44%), Endometrial (16-71%), Ovarian (1-11%), Gastric, Pancreatic, Biliary tract, Urinary tract, Small bowel, Brain, Sebaceous tumors, Prostate

MUTYH* Colorectal (up to 80%), Small bowel (up to 4%), Endometrial, Gastrointestinal polyps

NF1Neurofibromas, Brain tumors (2-15%), Pheochromocytomas (1-13%), Sarcomas (6-13%), Female breast, Gastrointestinal stromal tumor (GIST)

PALB2 Female breast (up to 58%), Male breast, Pancreatic, Ovarian

PMS2**Colorectal (11-20%), Endometrial (12-15%), Ovarian, Gastric, Pancreatic, Biliary tract, Urinary tract, Small bowel, Brain, Sebaceous tumors, Prostate

PTENFemale breast (25-85%), Thyroid (3-38%), Endometrial (5-28%), Colorectal, Renal, Melanoma, Gastrointestinal polyps

TP53Female breast (85%), Sarcoma-bone and soft tissue, Brain, Hematologic malignancies, Adrenocortical carcinoma, among others. Overall risk for cancer: up to 95% in females, 88% in males

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ATM Female breast (27-33%), Colorectal, Pancreatic, Prostate

BRIP1 Ovarian

CHEK2 Female breast, Male breast, Colorectal, Gastric, Prostate, Thyroid

RAD51C Ovarian, Female breast

RAD51D Ovarian, Female breast

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BARD1 Female breast, Ovarian

FANCC Female breast

NBN Female breast, Non-Hodgkin lymphoma, Prostate

POLD1 Colorectal, Endometrial, Colon polyps

RECQL Female breast

*Most commonly associated cancer/tumors listed; lifetime risks provided when available. Risks relate to carriers of a single pathogenic variant with the exception of MUTYH.

**Tumor spectrum is representative of Lynch syndrome; data are limited with regard to the association of certain cancers with pathogenic variants in MSH6, PMS2 and EPCAM.

Table 1: Lifetime Cancer and/or Tumor Risks for Genes Associated with Hereditary Breast and Gynecologic Cancer

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Influencing Factors on Cancer and/or Tumor RiskWhile individuals with pathogenic variants in these genes have increased risks of cancers and/or tumors compared to the general population, it is not a guarantee that a person will develop a cancer or tumors. In general, an individual’s risk to develop a specific cancer and/or tumor is dependent not only on genetic factors, but may also be influenced by environmental and lifestyle factors as well.

Breast Cancer Risk FactorsSeveral risk factors have been linked to breast cancer including lifestyle factors like diet, weight, exercise, smoking, and alcohol use. Other risk factors include age, a personal history of dense breast tissue, certain benign breast conditions, reproductive history, taking medications that contain hormones, and a family history of breast cancer, among others.

Ovarian Cancer Risk FactorsSeveral risk factors have been linked to ovarian cancer including lifestyle factors like diet and weight. Other risk factors include age, reproductive history, taking fertility or other medications that contain hormones, and a family history of ovarian cancer, among others.

Endometrial Cancer Risk Factors Several risk factors have been linked to endometrial cancer including lifestyle factors like diet, weight and exercise Other risk factors include age, reproductive history, taking Tamoxifen or other medications that contains hormones, being diagnosed with polycystic ovarian syndrome, and a family history of uterine cancer, among others.

7 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Identifying Patients at Risk for Hereditary Breast and Gynecologic Cancer Individuals with a personal and/or family history of the following may be at risk for hereditary breast, ovarian, and/or endometrial cancer. Family history includes first, second, and third-degree blood relatives (including parents, siblings, children, aunts/uncles, cousins, and grandparents).

• Breast or endometrial cancer diagnosed under 50 years of age

• Multiple cancers in one person, either of the same origin (such as two separate breast cancers) or of different origins (such as breast and ovarian cancer or endometrial and colon cancer)

• Ovarian cancer or male breast cancer at any age

• Multiple relatives diagnosed with the same or related cancers (including breast, ovarian, endometrial, pancreatic and/or prostate) on the same side of the family and spanning multiple generations

• Ashkenazi Jewish ancestry with a history of breast, ovarian or pancreatic cancer

• A known pathogenic variant in a blood relative

It is important to provide detailed information on the personal and family histories of cancer, including ages of diagnosis, pathology, and relationship between family members. This information can help determine if testing is appropriate and which test is medically necessary, as well as may impact insurance coverage.

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BRCA1/BRCA2 Ashkenazi Founder Panel (TAT 8-10 days) Targeted testing for three known founder variants in BRCA1 and BRCA2

BRCA1/BRCA2 Sequencing and Deletion/Duplication (TAT 8-10 days) BRCA1, BRCA2

Breast/Gyn Cancer Panel (TAT 2 weeks) ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FANCC, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, POLD1, PTEN, RAD51C, RAD51D, RECQL, TP53

Breast Cancer Management Panel (TAT 2 weeks; RUSH surgical cases 8-10 days) ATM, BRCA1, BRCA2, CDH1, CHEK2, NBN, PALB2, PTEN, TP53

Breast and Ovarian Cancer Testing Options

Breast/Gyn Cancer Panel (TAT 2 weeks) ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FANCC, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, POLD1, PTEN, RAD51C, RAD51D, RECQL, TP53

Lynch/Colorectal High Risk Panel (TAT 2 weeks) APC, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2

Endometrial Cancer Testing Options

Comprehensive Common Cancer Panel (TAT 2 weeks) APC, ATM, AXIN2, BAP1, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, FANCC, FH, FLCN, HOXB13, MET, MITF, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, NTHL1, PALB2, PMS2, POLD1, POLE, POT1, PTEN, RAD51C, RAD51D, RECQL, SCG5/GREM1, SDHB, SDHC, SDHD, SMAD4, STK11, TP53, TSC1, TSC2, VHL

OncoGeneDx Custom Panel (TAT 3 weeks) Create a customized cancer panel from a list of 64 cancer susceptibility genes. For a complete list of available genes, please visit our website at www.genedx.com/oncology.

Common Cancer Management Panel (TAT 2 weeks) APC, ATM, AXIN2, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDKN2A, CHEK2, EPCAM, FH, FLCN, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, NTHL1, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, SCG5/GREM1, SDHB, SDHC, SDHD, SMAD4, STK11, TP53, TSC1, TSC2, VHL

Panels for Multiple Cancer Types

Test OptionsBelow are the tests available for individuals at risk for hereditary breast and gynecologic cancer.

9 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Additional testing options are available, including targeted variant testing for a previously identified pathogenic or likely pathogenic variant in a family member. For a complete list of available testing options, please visit our website at www.genedx.com/oncology. Appropriate test selection depends on the specific clinical history of a patient, including family history of cancer and/or previous personal or familial test results. Testing for most genes includes sequencing and deletion/duplication analysis via next-generation sequencing.

Sample Submission Genetic testing can be performed on blood, oral rinse, buccal swab or extracted DNA samples. GeneDx test kits are available to ordering providers, and include sample collection items (such as collection tubes, mouthwash for oral rinse samples, and sponges for a buccal swab), the necessary sample submission paperwork, and a self-addressed return shipping label.

GeneDx is committed to providing an easy to use online platform to order genetic tests. Our online portal makes the ordering process simple and straightforward. Providers can now upload clinical information electronically, track the progress of an order, and receive results instantaneously through the portal. The portal can be accessed from our website www.genedx.com. Additionally, GeneDx forms can also be easily accessed for digital or print use at www.genedx.com/forms.

Please note that all testing must be performed under the guidance of a healthcare provider. For more information on the sample submission process, please visit our website: www.genedx.com/supplies or email us at: zebras@genedx.com

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Genetic Testing Process

The health care provider and the patient discuss the test results, medical management options, and implications for family members

The patient’s sample and necessary paperwork are sent to the laboratory

Genetic Test Results

Post-Test Discussion

Sample Submission

Genetic Testing

Discussion of personal and family history

Explanation of genetic testing options

At the laboratory, genetic testing for most genes includes next-generation sequencing and/or exon array analysis

Contains information on the results of the genetic test and available medical management options

The final report is sent to the ordering healthcare provider

BRCA1/2 NegativeInformation for Patients Who Have Tested Negative for a Pathogenic VariantYour Genetic Test Results:

You have undergone genetic testing to detect changes in the BRCA1 and BRCA2 genes, which are associated with an increased risk forbreast, ovarian and other types of cancer. Your test was negative for any pathogenic (harmful) variants.

What This Test Result Means

For You:If you have had a diagnosis of cancer, the reason why you developed cancer remains unknown. It is possible that you have a pathogenicvariant in an untested area of the BRCA1 or BRCA2 gene or you have a pathogenic variant in a different gene. It is also possible that yourcancer was caused by factors other than your genes. You should continue your medical management as recommended by your doctor.

If you have never had a cancer diagnosis, and have undergone testing based on a family history of cancer with no known pathogenicvariant in the family, this result does not provide an explanation for the cancer in your family. Your risk to develop cancer may still beincreased, and you should continue with medical management based on your medical and/or family history. Your result may be negativebecause there is a genetic predisposition in your family that you did not inherit or it may be that the cancer in your family is caused bysomething beyond the genes included in this test. To clarify which of these explanations is more likely, it may be helpful to test amember of your family who has been diagnosed with cancer in order to determine if the cause of the cancer in your family can beidentified. Testing other family members may also help to clarify your risk of developing cancer.

For Your Family:Although your testing was negative, your family members may still be at increased risk for developing cancer. If a genetic cause for thecancer in you and/or your family has not been identified, genetic testing for family members who have not been diagnosed with cancermay not be useful. In some cases, it may be helpful for other relatives with a cancer diagnosis to undergo this testing, particularly ifdiagnosed at a young age or with a less common type of cancer such as ovarian cancer.

Share a copy of your test report with your biologic family members, so that their doctor knows which genes were tested.

If your family members would like to learn more about their risk for developing cancer, genetic counseling is recommended. The NationalSociety of Genetic Counselors maintains a list of national and international genetic counselors. Visit www.nsgc.org to locate a geneticcounselor near you.

Medical Management Options

There are a variety of management strategies available to individuals at an increased risk to develop breast, ovarian and other types ofcancer based on genetic test results and/or personal or family history risk factors. Medical management varies for each patient, and youshould discuss your specific options with your doctor.

Glossary

Gene: A defined segment of DNA that provides instructions for the cells of the body to make a specific protein.

Genetic: Refers to a medical condition that is caused, at least in part, by an alteration (or pathogenic variant) in a person’s DNA. Geneticconditions are often inherited, or passed down through the family tree.

Pathogenic Variant: An alteration in DNA considered to increase the risk for or cause the development of a particular disease.

Resources• Facing Our Risk of Cancer Empowered (FORCE): www.facingourrisk.org• Bright Pink: www.brightpink.org• National Cancer Institute: www.cancer.gov/ cancertopics/genetics• GeneDx: www.oncogenedx.com

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© 2017 GeneDX. All rights reserved. 91462 4/2017Information current as of 9/2015

Oncology Genetic Test Report

Comprehensive Cancer Panel

Final Report

P A T I E N TS A M P L E

P H Y S I C I A N

PHYSICIAN

ACCT #

NAMEDOB: Age: Sex:

Ethnicity:

Patient ID:

Address:

Specimen ID:

Date of Report: 4/19/17

Date Collected:

Date Received:

Source:

Additional Healthcare Provider:

Comprehensive Cancer Panel

APC, ATM, AXIN2, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2,

EPCAM, FANCC, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D,

SCG5/GREM1, SMAD4, STK11, TP53, VHL, XRCC2 (32 genes)Genes Evaluated:

Personal history of signet ring gastric cancer. Family history of stomach and other cancer.

Test Indication

Results Summary: POSITIVE

GeneVariant

ClassificationZygosity

CHEK2c.1100delC (p.Thr367MetfsX15) PATHOGENIC

HETEROZYGOUS

No additional reportable variants were detected by sequencing or deletion/duplication analysis of any of the genes on

this panel.

Clinical Summary

This individual is heterozygous for a pathogenic variant in CHEK2, consistent with an increased risk for breast cancer

in women and other cancers in both women and men. See interpretation for detailed clinical summary.

Recommendations

Genetic counseling is recommended to discuss the implications of these results.

•The NCCN Guidelines for Genetic/Familial High-Risk Assessment: (Breast/Ovarian and Colorectal) include

management recommendations for individuals with pathogenic variants in CHEK2.

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First degree relatives have up to a 50% chance of also having the pathogenic variant identified in this individual.

Targeted testing for the pathogenic variant(s) is available for at-risk relatives.

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If you would like to discuss these results in further detail, please call one of our genetic counselors.

•GenomeConnect is an NIH initiative created to enable individuals and families with the same genetic variant or

medical history to connect and share de-identified information. If you are interested in participating, please visit

www.genomeconnect.org.•

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Report Electronically Signed By:

Brandi A. Thompson, PhD, MB(ASCP)CM,

DABMGGClinical Molecular Geneticist

Report Electronically Signed By:

Kristin Theobald, MS, CGC

Genetic Counselor

Anne Maddalena, Ph.D., FACMG

Laboratory Director

GeneDx 207 Perry Parkway, Gaithersburg, MD 20877 P: (888) 729-1206 F: (301) 710-6594 genedx.com/oncology

GeneDx is a business unit of BioReference Laboratories, Inc.

Patient Identification

11 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Genetic Test ResultsNearly all test results fall into one of four categories: positive (pathogenic variant), likely pathogenic variant, negative and a variant of uncertain significance (VUS). Genetic counseling is recommended prior to and following genetic testing to understand the benefits and limitations of testing.

Positive Result A positive result indicates a genetic variant (change) was identified in a specific gene and that variant is pathogenic (harmful). With a positive test result, the risk to develop a particular disease (in this case, cancer and/or tumors) is increased. The lifetime risk for cancer and/or tumors depends on which gene was identified as having the pathogenic variant.

Knowledge of a positive result provides valuable information to patients, healthcare providers, and family members as they develop a medical management plan. Results may direct treatment of a current cancer diagnosis or reduce the risk for or improve early detection of future cancers and/or tumors. A medical management plan may include enhanced screening or in some cases, risk-reducing surgery and/or medication. Furthermore, testing family members may be appropriate and can allow for more accurate predictions of their cancer and/or tumor risks.

Likely Pathogenic Variant Result A likely pathogenic variant result indicates that there is a variant in a specific gene for which there is significant, but not conclusive, evidence of an increased risk to develop a particular disease (in this case, cancer and/or tumors). The lifetime risk for cancer and/or tumors depends on which gene was identified as having the likely pathogenic variant. With this type of result, a medical management plan may include similar options as described above for a positive result, including enhanced screening, risk-reducing options and testing of family members.

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Oncology Genetic Test ReportComprehensive Cancer Panel

Final Report

P A T I E N T S A M P L EP H Y S I C I A NPHYSICIAN

ACCT #

NAMEDOB: Age: Sex: Ethnicity: Patient ID:Address:

Specimen ID: Date of Report: 4/19/17 Date Collected:Date Received: Source:

Additional Healthcare Provider:

Comprehensive Cancer Panel APC, ATM, AXIN2, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A, CHEK2,EPCAM, FANCC, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D,SCG5/GREM1, SMAD4, STK11, TP53, VHL, XRCC2 (32 genes)

Genes Evaluated:

Personal history of signet ring gastric cancer. Family history of stomach and other cancer.Test Indication

Results Summary: POSITIVEGene Variant Classification ZygosityCHEK2 c.1100delC (p.Thr367MetfsX15) PATHOGENIC HETEROZYGOUSNo additional reportable variants were detected by sequencing or deletion/duplication analysis of any of the genes onthis panel.Clinical SummaryThis individual is heterozygous for a pathogenic variant in CHEK2, consistent with an increased risk for breast cancerin women and other cancers in both women and men. See interpretation for detailed clinical summary.

RecommendationsGenetic counseling is recommended to discuss the implications of these results.•The NCCN Guidelines for Genetic/Familial High-Risk Assessment: (Breast/Ovarian and Colorectal) includemanagement recommendations for individuals with pathogenic variants in CHEK2.

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First degree relatives have up to a 50% chance of also having the pathogenic variant identified in this individual.Targeted testing for the pathogenic variant(s) is available for at-risk relatives.

•

If you would like to discuss these results in further detail, please call one of our genetic counselors.•GenomeConnect is an NIH initiative created to enable individuals and families with the same genetic variant ormedical history to connect and share de-identified information. If you are interested in participating, please visitwww.genomeconnect.org.

•

Page 1 of 4

Report Electronically Signed By:Brandi A. Thompson, PhD, MB(ASCP)CM,DABMGGClinical Molecular Geneticist

Report Electronically Signed By:Kristin Theobald, MS, CGCGenetic Counselor

Anne Maddalena, Ph.D., FACMGLaboratory Director

GeneDx 207 Perry Parkway, Gaithersburg, MD 20877 P: (888) 729-1206 F: (301) 710-6594 genedx.com/oncologyGeneDx is a business unit of BioReference Laboratories, Inc.

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Negative Result A negative result means that no reportable variants were identified. This result can have different implications depending on the specific circumstances related to the testing.

In many cases when no one in the family has previously been found to have a pathogenic variant, the reason for the patient’s personal or family

history of cancer remains unknown. The result may be negative because there is a genetic predisposition in the family that the patient did not inherit or it may be that the cancers and/or tumors in the family are caused by something beyond the genes included on their test. The risk for future cancers and medical management recommendations should be based on personal and/or family history of cancer.

When an individual tests negative for a familial pathogenic variant that has already been identified in another family member, this is considered a true negative test result. In most cases, the risk for cancer is not expected to be greater than the general population. Sometimes this interpretation may be limited if the family member’s pathogenic variant was identified in a gene described as moderate-risk or newer-risk.

Depending upon the patient’s personal and family history of cancer, additional genetic testing may be indicated for the patient or a family member. Sometimes there are other genes that can explain the family history of cancer, or areas of a gene which were not examined with the initial test. A genetic specialist or other healthcare provider can determine if further genetic testing is appropriate.

Variant of Uncertain Significance (VUS) ResultA variant of uncertain significance (VUS) result means that a change in a specific gene was identified, however the effect of the variant cannot be clearly established. There may be conflicting or incomplete information in the medical literature about this variant and its association with an increased risk of cancers and/or tumors is unknown. In other words, it cannot be determined yet whether this variant is associated with an increased risk of cancer and/or tumors or it is a harmless (normal)

BRCA1/2 NegativeInformation for Patients Who Have Tested Negative for a Pathogenic VariantYour Genetic Test Results:

You have undergone genetic testing to detect changes in the BRCA1 and BRCA2 genes, which are associated with an increased risk forbreast, ovarian and other types of cancer. Your test was negative for any pathogenic (harmful) variants.

What This Test Result Means

For You:If you have had a diagnosis of cancer, the reason why you developed cancer remains unknown. It is possible that you have a pathogenicvariant in an untested area of the BRCA1 or BRCA2 gene or you have a pathogenic variant in a different gene. It is also possible that yourcancer was caused by factors other than your genes. You should continue your medical management as recommended by your doctor.

If you have never had a cancer diagnosis, and have undergone testing based on a family history of cancer with no known pathogenicvariant in the family, this result does not provide an explanation for the cancer in your family. Your risk to develop cancer may still beincreased, and you should continue with medical management based on your medical and/or family history. Your result may be negativebecause there is a genetic predisposition in your family that you did not inherit or it may be that the cancer in your family is caused bysomething beyond the genes included in this test. To clarify which of these explanations is more likely, it may be helpful to test amember of your family who has been diagnosed with cancer in order to determine if the cause of the cancer in your family can beidentified. Testing other family members may also help to clarify your risk of developing cancer.

For Your Family:Although your testing was negative, your family members may still be at increased risk for developing cancer. If a genetic cause for thecancer in you and/or your family has not been identified, genetic testing for family members who have not been diagnosed with cancermay not be useful. In some cases, it may be helpful for other relatives with a cancer diagnosis to undergo this testing, particularly ifdiagnosed at a young age or with a less common type of cancer such as ovarian cancer.

Share a copy of your test report with your biologic family members, so that their doctor knows which genes were tested.

If your family members would like to learn more about their risk for developing cancer, genetic counseling is recommended. The NationalSociety of Genetic Counselors maintains a list of national and international genetic counselors. Visit www.nsgc.org to locate a geneticcounselor near you.

Medical Management Options

There are a variety of management strategies available to individuals at an increased risk to develop breast, ovarian and other types ofcancer based on genetic test results and/or personal or family history risk factors. Medical management varies for each patient, and youshould discuss your specific options with your doctor.

Glossary

Gene: A defined segment of DNA that provides instructions for the cells of the body to make a specific protein.

Genetic: Refers to a medical condition that is caused, at least in part, by an alteration (or pathogenic variant) in a person’s DNA. Geneticconditions are often inherited, or passed down through the family tree.

Pathogenic Variant: An alteration in DNA considered to increase the risk for or cause the development of a particular disease.

Resources• Facing Our Risk of Cancer Empowered (FORCE): www.facingourrisk.org• Bright Pink: www.brightpink.org• National Cancer Institute: www.cancer.gov/ cancertopics/genetics• GeneDx: www.oncogenedx.com

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variant. In some cases, it may be helpful to test other family members through our Variant Testing Program to help clarify the risk. Over time, the VUS may become reclassified to either a “positive” or “negative” test result. The patient’s risk for future cancers and medical management recommendations should typically be based on personal and/or family history until the VUS is reclassified.

Test ReportsTest reports contain detailed information about a specific genetic result and, if available, medical management options. Additional support is available from our laboratory genetic counselors and local genetic providers within your area. Genetic counseling services can be found at www.nsgc.org within the United States or www.cagc-accg.ca in Canada.

Test results are available within 2-3 weeks after a sample is received in the laboratory. Once complete, test results are sent to the ordering healthcare provider. The healthcare provider should share those results and discuss them in the context of the reported personal and family histories.

Medical Management Based on Genetic Test ResultsMedical management options for early detection or risk reduction are available for many individuals found to have a pathogenic variant in a gene associated with hereditary cancer. The options may include enhanced screening, risk reducing surgery, and in some cases, risk reducing medication. Options for screening and risk reduction are based on national guidelines or consensus statements, when available, and are specific to the gene in which a pathogenic variant is identified.

Information on screening and risk reduction options are included in the report for a positive and likely pathogenic test result. A summary of medical management options are provided in Table 2.

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Gene Medical Management Guidelines

ATM4

• Breast awareness• Clinical encounter, including clinical breast examination• Breast MRI and mammogram • Consider individualized prostate cancer screening based on personal and/or

family history

BRCA1, BRCA24

• Breast awareness, including breast self-examination for both men and women• Clinical encounter, including clinical breast examination for both men and women• Breast MRI and mammography starting at an early age• Consider prophylactic mastectomy• Bilateral Salpingo-Oophorectomy (BSO)• Consider transvaginal ultrasound of ovaries and CA-125 blood tests for women

who have not had a BSO• Consider the use of risk-reducing medications (such as tamoxifen, raloxifene and

oral contraceptives)• Prostate cancer screening starting at an early age• Consider pancreatic cancer screening and full body skin examination dependent

on family history

For BRCA2 only• Consider individualized melanoma screening based on personal and/or family

history

BRIP14 • Consider bilateral salpingo-oophorectomy

CDH14,6

• Breast awareness• Clinical encounter, including clinical breast examination• Breast MRI and mammography starting at an early age• Consider prophylactic mastectomy, not routinely recommended but may be

reasonable for some women• Consider the use of risk-reducing medications (such as tamoxifen or raloxifene)• Prophylactic gastrectomy• In the absence of gastrectomy, upper endoscopy• Consider colonoscopy starting at an early age, dependent on family history

CHEK24,7

• Breast awareness• Clinical encounter, including clinical breast examination • Breast MRI and mammogram • Periodic colonoscopy starting at an early age*• Consider individualized prostate cancer screening based on personal and/or

family history

Table 2: Medical Management Options for Genes Associated with Hereditary Breast and Gynecologic Cancer

15 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Gene Medical Management Guidelines

EPCAM, MLH1, MSH2, MSH6, PMS27

• Frequent colonoscopy (every 1-2 years in many cases) starting at an early age• Consider the option of prophylactic colectomy, particularly if surgery is required

to address a colonic neoplasm or if frequent colonoscopy is not an optimal option for surveillance

• Consider endometrial/ovarian cancer screening, which may include endometrial biopsy, transvaginal ultrasound and CA-125 blood tests

• Consider prophylactic hysterectomy and bilateral salpingo-oophorectomy once a woman has completed childbearing

• Consider the use of risk-reducing medications such as hormonal contraception• Consider periodic upper endoscopy with extended duodenoscopy• Consider urinalysis to screen for urinary tract cancers• Consider physical examination with neurological examination• Consider individualized prostate cancer screening based on personal and/or

family history

MUTYH7

For 2 pathogenic variants• Frequent colonoscopy starting at an early age• Baseline upper endoscopy with duodenoscopy• Colectomy is generally recommended for individuals who have adenomas that

cannot be managed through colonoscopy• Physical examination

For 1 pathogenic variants• Consider periodic colonoscopy starting at an early age, dependent on family

history

NBN4

• Breast awareness• Clinical encounter, including clinical breast examination• Breast MRI and mammogram • Consider individualized prostate cancer screening based on personal and/or

family history

NF14,8

• Developmental assessment• Blood pressure monitoring • Monitoring of abnormalities of the central nervous system, skeletal system, or

cardiovascular system by an appropriate specialist• Other studies (e.g., MRI) as indicated based on signs or symptoms• Physical and ophthalmologic examinations• Breast awareness• Clinical encounter, including clinical breast examination• Breast MRI and mammogram starting at an early age• One or more management recommendations may begin in childhood or

adolescence

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Gene Medical Management Guidelines

PALB24,9

• Breast awareness• Clinical encounter, including clinical breast examination• Breast MRI and mammogram starting at an early age• Consider pancreatic cancer screening dependent on family history

POLD17

• Frequent colonoscopy starting at an early age; if adenomas are identified, increase the interval of colonoscopy*

• Colectomy may be appropriate for individuals who have adenomas that cannot be managed through colonoscopy*

PTEN4

• Breast awareness, including breast self-examination• Clinical encounter, including clinical breast examination• Breast MRI and mammography starting at an early age• Consider endometrial biopsy and/or transvaginal ultrasound; encourage patient

education and prompt response to symptoms • Options of prophylactic mastectomy and hysterectomy can be discussed• Periodic colonoscopy starting at an early age• Thyroid ultrasound • Consider renal ultrasounds• Physical examination• Consider dermatological examination• One or more management recommendations may begin in childhood or

adolescence

RAD51C,RAD51D4 • Consider bilateral salpingo-oophorectomy

TP534

• Breast awareness, including breast self-examination• Clinical encounter, including clinical breast examination• Breast MRI and mammography starting at an early age• Consider prophylactic mastectomy• Consider periodic colonoscopy starting at an early age• Consider whole body MRI, including brain imaging• Comprehensive physical examination, including neurologic and skin examination

starting at an early age• Use caution regarding radiation therapy for cancer• Additional surveillance based on family history of cancer• One or more management recommendations may begin in childhood or

adolescence

*Given limited data to support these guidelines, caution should be used when making recommendations.

For the details on the specific medical management options, including frequency of screening and ages to begin surveillance, please review the referenced guidelines or consensus statements.

17 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Implications for Family MembersRegardless of the result, patients should share their test report with their blood relatives, who can then discuss the results with their healthcare providers. Sharing a copy of the test result with family members and healthcare providers will help to determine if additional testing is necessary and will ensure that the proper test is ordered for relatives, if indicated.

For most positive or likely pathogenic test results, first-degree relatives (including parents, siblings, and children) have a 50% chance to have the same variant. The risk for other family members to carry the variant depends on how closely related they are to the person with a positive or likely pathogenic test result. It is important to remember that for most of these genes, not all people who inherit a pathogenic or likely pathogenic variant will develop cancer and/or tumors, but the chance is increased above that of the general population.

In some cases, certain genes may also be associated with an autosomal recessive condition. This occurs when an individual inherits two pathogenic variants, one from each parent. For most autosomal recessive conditions, the two pathogenic variants occur within the same gene and affect both copies of that gene. The genes associated with autosomal recessive conditions include ATM, BRCA2, BRIP1, FANCC, FH, MUTYH, NBN, NTHL1, PALB2, POLE, RAD51C, SDHA, SDHB, SDHD, SMARCA4, SMARCB1 and the Lynch syndrome genes (EPCAM, MLH1, MSH2, MSH6 and PMS2). When an individual has two variants in these genes, the cancer and/or tumor risks and the risks to family members are different than described above. In the case of a positive result, the report will provide additional information on the gene, inheritance and cancer and/or tumor risks.

Genetic CounselingPrior to genetic testing, patients should speak to their healthcare provider and/or a genetic specialist about their personal and family history of cancer, allowing for cancer risk assessment. Healthcare providers should discuss the benefits and limitations of testing, as well as possible test results. These conversations help to determine if the patient meets clinical criteria for testing, facilitates appropriate test ordering and ensures that the patient has provided informed consent for genetic testing.

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If a pathogenic variant has already been identified in a family member, testing of the specific variant is appropriate. If a pathogenic variant has never been identified, an affected family member with the highest likelihood for a positive result (such as having early-onset disease, bilateral disease or multiple primaries) is ideally the best person for initial testing within a family. If an affected family member is not available, testing of an unaffected family member can be considered, although a negative test result will not guarantee that the individual does not have an increased risk for cancer and/or tumors.

Once a patient makes the decision to undergo testing, post-test genetic counseling is recommended to understand the implications of the results, including discussion of cancer risks and appropriate medical management based on both the test results and the patient’s medical and family histories. Genetic counseling services can be found at www.nsgc.org within the United States or www.cagc-accg.ca in Canada.

Insurance Coverage and Cost for Genetic TestingGeneDx accepts all commercial plans and is a Medicare provider. Additionally, GeneDx is a registered provider with several Medicaid plans. If a patient does not have health insurance or cannot afford to pay the cost of testing, GeneDx provides a financial assistance program to help ensure that all patients have access to medically necessary genetic testing.

For more information on the paperwork that is required by some insurance carriers, as well as additional details on patient billing or our financial assistance program, please visit our website: www.genedx.com and click on the “Billing” tab.

19 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

General

American Cancer Society www.cancer.org

GeneDx www.genedx.com/oncology

National Cancer Institute www.cancer.gov

Breast/Gyn Cancer

Bright Pink www.brightpink.org

Facing Our Risk of Cancer Empowered (FORCE) www.facingourrisk.org

Colon Cancer Alliance www.ccalliance.org

Fight Colorectal Cancer www.fightcolorectalcancer.org

Hereditary Colon Cancer Takes Guts www.hcctakesguts.org

Colon Cancer Alliance for Research and Education for Lynch Syndrome (CCARE) www.fightlynch.org

Find a Genetic Counselor

Canadian Association of Genetic Counsellors www.cagc-accg.ca

National Society of Genetic Counselors www.nsgc.org

Resources

Genetic Information Nondiscrimation ActThe Genetic Information Nondiscrimination Act of 2008, also referred to as GINA, is a federal law that protects Americans from discrimination by health insurance companies and employers based on their genetic information. However, this law does not cover life insurance, disability insurance, or long-term care insurance. GINA’s employment protections do not extend to individuals in the U.S. military, federal employees, Veterans Health Administration and Indian Health Service. Some of these organizations may have internal policies to address genetic discrimination. For more information, please visit: http://www.ginahelp.org/GINAhelp.pdf

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ReferencesFor a complete list of references by gene used for our educational and patient materials please visit our website at www.genedx.com/oncology and click on the “Resources” tab.

1. Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. SEER Cancer Statistics Review,1975-2012: Lifetime Risk Tables (URL: http://surveillance.cancer.gov/devcan) [November 2017 accessed]

2. Hampel H et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genetics in Medicine 2015; 17: 70–87.

3. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genetics in Medicine 2016; 18: 823–832.

4. NCCN Guidelines. Genetic/Familial High-Risk Assessment: Breast and Ovarian. URL: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp) [October 2017 accessed].

5. NCCN Guidelines. Gastric Cancer. (URL:https://www.nccn.org/professionals/ physician_gls/pdf/ gastric.pdf) [July 2017 accessed]

6. van der Post RS, Vogelaar IP, Carneiro F, et al. Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers. J Med Genet 2015; 52:361-374.

7. NCCN Guidelines. Genetic/Familial High-Risk Assessment: Colorectal. (URL: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp) [August 2017 accessed].

8. Friedman JM. Neurofibromatosis 1. 1998 Oct 2 [Updated 2014 Sep 4]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1109/

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 Mar;62(3):339-47.

21 GUIDE FOR HEREDITARY BREAST & GYNECOLOGIC CANCER

Notes

About GeneDx

GeneDx was founded in 2000 by two scientists from the National Institutes of Health (NIH) to address the needs of patients diagnosed with rare disorders and the clinicians treating these conditions. Today, GeneDx has grown into a global industry leader in genomics, having provided testing to patients and their families in over 55 countries. Led by its world-renowned clinical genomics program, and an unparalleled comprehensive genetic testing menu, GeneDx has a continued expertise in rare and ultra-rare disorders. Additionally, GeneDx also offers a number of other genetic testing services, including: diagnostic testing for hereditary cancers, cardiac, mitochondrial, and neurological disorders, prenatal diagnostics, and targeted variant testing. At GeneDx, our technical services are backed by our unmatched scientific expertise and our superior customer support. Our growing staff includes more than 35 geneticists and 140 genetic counselors specializing in clinical genetics, molecular genetics, metabolic genetics, and cytogenetics who are just a phone call or email away to assist you with your questions and testing needs. We invite you to visit our website: www.genedx.com to learn more about us.

© 2017 GeneDx, Inc. All rights reserved. 40002 V2 12/17 Information current as of 12/17

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