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Gene test interpretation: BRCA1 and BRCA2

Gene test interpretation: BRCA1 and BRCA2
Literature review current through: Jan 2024.
This topic last updated: Sep 20, 2023.

INTRODUCTION — This monograph summarizes interpretation of germline testing of BRCA1 and BRCA2 genes. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately [1]. (See 'UpToDate topics' below.)

OVERVIEW

How to read the report — The checklist summarizes an approach to reviewing the report (table 1). Considerations include extent of testing, accuracy of variant identification, and interpretation:

Extent of testing – Most laboratories perform comprehensive sequencing of BRCA1 and BRCA2 genes; however, it is important to determine whether the entire gene, coding regions, or selected variants were evaluated.

Comprehensive testing can identify thousands of variants, including many that are clearly established as pathogenic or benign. Most individuals should be offered comprehensive sequencing of BRCA1 and BRCA2 regardless of their familial variant or ancestry because pathogenic variants are seen in the general population, and compound heterozygotes have been identified unexpectedly.

Accuracy – Laboratories are certified according to the Clinical Laboratory Improvement Amendments (CLIA). If results were obtained by direct-to-consumer testing or research, testing should be repeated, possibly with additional gene tests, in a CLIA-certified laboratory or other nationally certified laboratory. This is particularly true if test results would impact clinical care of the patient and/or relatives, such as a pathogenic variant in a gene with known clinical significance that is potentially clinically actionable, or a negative finding in an individual with a suspected cancer syndrome.

Interpretation – Pathogenicity is classified based on established criteria. The interpretation may require updating, particularly for a variant of uncertain significance (VUS). (See 'Classification of variants' below.)

The table provides a glossary of genetic testing terms (table 2).

Classification of variants — The pathogenicity of each variant is classified by the laboratory into one of five categories (table 3), using information available at the time [2]. The classification for many variants continues to be updated, especially for VUS, as more evidence from research becomes available [3]. The uncertainty reflects the available data on the role of the variant rather than the accuracy of genotyping.

If there is concern about the classification, such as for a VUS or low-penetrance variant, obtain an updated interpretation periodically (eg, annually) or when clinical management decisions might be altered. This can be done by checking a database such as ClinVar, contacting the laboratory, or consulting a specialist, clinical geneticist, or genetic counselor (see 'Locating a genetics expert' below); there is no gold standard approach.

Some laboratories routinely provide updates; others provide more information only when requested. Many VUS are reclassified as benign.

Likely benign and benign variants are not routinely reported (or are reported as negative); however, this information may be noted when a VUS is downgraded.

Disease associations — Pathogenic and likely pathogenic variants in BRCA1 and BRCA2 are associated with increased risk for several cancers (table 4). This is traditionally referred to as hereditary breast and ovarian cancer (HBOC) syndrome, although there are other increased risks including prostate cancer and pancreatic cancer [4].

BRCA1- or BRCA2-associated HBOC syndrome is autosomal dominant with incomplete penetrance (table 2). A pathogenic variant in either gene inherited from one parent increases the risk for the associated cancers; however, not all individuals with a variant will develop cancer. The tested individual's risk increases with age. Disease penetrance can also be modified by family history, other gene variants, and acquired risk factors. (See "Factors that modify breast cancer risk in women".)

Rarely, biallelic pathogenic variants in BRCA2 are associated with Fanconi anemia (FA), and biallelic pathogenic variants in BRCA1 are associated with a FA-like syndrome. (See "Clinical manifestations and diagnosis of Fanconi anemia", section on 'Genetics'.)

PEOPLE WITHOUT CANCER

Implications of a pathogenic or likely pathogenic variant — We treat pathogenic and likely pathogenic variants in BRCA1 and BRCA2 the same for counseling and risk management, regardless of the reason for testing and family history.

Discussion includes the cancer risks (table 4), possible interventions for surveillance or risk reduction (table 5), reproductive counseling, and implications for at-risk relatives (see 'Other considerations' below). Risks depend on the person's age.

Counseling may require additional visits or referral to a specialist; management decisions can be deferred until questions have been answered.

We adhere to the National Comprehensive Cancer Network (NCCN) recommendations for surveillance and risk reduction [5]. Cancer type and age of onset in family members may inform screening (earlier screening if a relative has earlier onset).

Several surveillance and risk reduction strategies exist (table 5). Use depends on the patient's age, values and preferences, and, for females, desire for childbearing (algorithm 1).

Breast cancer:

Females:

Increased surveillance:

-Breast awareness and self-examination starting at age 18.

-Clinical breast examination every 6 to 12 months starting at age 25.

-Annual magnetic resonance imaging (MRI) with contrast starting at age 25 to 29 (or individualized based on family history).

-Annual mammography with consideration of tomosynthesis starting at age 30.

-Individualized management after age 75.

Discussion of risk-reducing bilateral mastectomy, with shared decision-making [6].

Hormonal chemoprevention (tamoxifen or an aromatase inhibitor) may be offered if risk-reducing mastectomy was not performed; however, efficacy data are very limited.

Males:

Breast self-examination and annual clinical breast examination starting at age 35.

Consider annual mammography, especially those with a pathogenic or likely pathogenic variant in BRCA2, starting at age 50 or 10 years before the earliest known male breast cancer in the family, whichever comes first.

Ovarian and other gynecologic cancers:

Recommendation for risk-reducing bilateral salpingo-oophorectomy (rrBSO)

-Generally at age 35 to 40 for BRCA1 carriers

-At age 40 to 45 for BRCA2 carriers

-Earlier if indicated based on age at ovarian cancer diagnosis in a relative

Females are encouraged to complete childbearing by these ages; otherwise, surgery may be performed after childbearing is complete [6]. (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Risk-reducing surgery'.)

Consideration for transvaginal ultrasound and CA-125 for females who do not elect rrBSO, with a discussion of the uncertain benefits of this approach.

Discussion of the risks and benefits of hysterectomy at the time of rrBSO [6].

Discussion of hormone therapy for menopausal symptoms and possibly other health risks associated with early menopause.

Prostate cancer:

For BRCA2 carriers, prostate cancer surveillance starting at age 40, including prostate-specific antigen (PSA) and digital rectal examination. For BRCA1 carriers, discussion of the risks and benefits of prostate cancer screening starting at age 40. (See "Genetic risk factors for prostate cancer", section on 'Screening implications of increased genetic risk'.)

Pancreatic cancer:

Periodic screening for pancreatic cancer is appropriate for those with a family history of pancreatic cancer; usually includes contrast-enhanced magnetic resonance imaging (MRI)/magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic ultrasound. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients".)

Melanoma:

Consideration of annual full body skin examinations. For those with a pathogenic or likely pathogenic variant in BRCA2, notification of the eye care provider about the possible increased risk of ocular melanoma. (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Screening for other cancers'.)

Implications of a negative test — Negative testing means no pathogenic variants were identified (algorithm 1). However, some tests may be inconclusive or may not cover all possible variants.

Once a pathogenic variant is identified in a relative and the tested individual is demonstrated not to have that variant, they usually can be reassured that they are not at high risk for associated cancers, with the caveats above. (See 'How to read the report' above.)

However, an individualized assessment is important, to consider factors such as the presence of non-BRCA1/2-associated cancers on the side of the family with the pathogenic variant, cancer history on the side of the family without the variant, as well as other personal cancer risk factors.

For some individuals, testing with a multi-gene cancer panel is recommended rather than testing only for the familial variant, BRCA1/2 only, or only the Ashkenazi Jewish founder pathogenic variants in BRCA1/2.

If a pathogenic variant in a family has not been identified and genetic testing is negative, additional risk factors (genetic or acquired) may be present. If there is a strong suspicion of a familial cancer syndrome, such individuals, as well as those who do not have documentation of a familial variant, should undergo comprehensive testing (with a multi-gene cancer panel). Surveillance and risk reduction recommendations are based on personal risk factors and family history. Referral may be helpful to determine optimal testing if family history is suggestive of a hereditary cancer syndrome. (See 'Locating a genetics expert' below.)

Implications of a VUS — Individuals with a variant of uncertain significance (VUS) should not be managed as though they have a pathogenic or likely pathogenic variant. Management should be based on their personal and family history (algorithm 1).

The testing laboratory or other resource should be consulted periodically for updates in the classification (eg, annually). (See 'Classification of variants' above.)

PEOPLE WITH CANCER — Genetic test results should be discussed with the oncologist or surgeon; referral to a specialist in hereditary breast and ovarian cancer may be appropriate. Implications may include:

More extensive breast cancer surgery (bilateral mastectomy to reduce the risk of a second primary breast cancer).

Incorporation of a poly-ADP-ribose polymerase (PARP) inhibitor for several different cancer types (eg, metastatic breast, prostate, pancreatic, and ovarian cancer).

Decisions about active surveillance versus local treatment for early-stage prostate cancer, given that BRCA1/2-associated prostate cancers tend to be more aggressive and have a poorer prognosis than those in the general population.

Additional surveillance and risk reduction. (See 'Implications of a pathogenic or likely pathogenic variant' above.)

Genetic counseling and testing of adult relatives is recommended. (See 'Other considerations' below.)

For individuals with a negative test or a variant of uncertain significance (VUS) for whom there are reasons to be concerned about a genetic cause, additional genetic testing may be appropriate and can be discussed with a genetic counselor, the primary oncologist, or other specialists. (See 'Locating a genetics expert' below.)

OTHER CONSIDERATIONS

Reproductive counseling — Preconception counseling is appropriate for individuals with a pathogenic or likely pathogenic variant in BRCA1 or BRCA2 who are considering childbearing.

Some may elect to use donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). Some may elect prenatal diagnosis. (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)

At-risk relatives — Individuals with a pathogenic variant or likely pathogenic variant should inform their at-risk relatives about the importance of genetic counseling and possible testing.

The risk of inheriting the variant is 50 percent for first-degree relatives (siblings and children). Other at-risk relatives may include aunts, uncles, nieces, nephews, and cousins.

Usually the variant segregates on the side of the family with a history of associated cancer(s); however, if possible, it is recommended to test a parent or other relative with cancer to determine the at-risk side of the family.

BRCA1 and BRAC2-associated cancers rarely occur before adulthood. Genetic testing can be deferred until age ≥18 years to allow autonomous decision-making and informed consent. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

Resources are listed below. (See 'Family communication' below.)

RESOURCES

UpToDate topics

Cancer risks – (See "Cancer risks and management of BRCA1/2 carriers without cancer".)

Genetic testing – (See "Genetic testing and management of individuals at risk of hereditary breast and ovarian cancer syndromes".)

Breast cancer – (See "Factors that modify breast cancer risk in women" and "ER/PR negative, HER2-negative (triple-negative) breast cancer" and "Overview of the approach to metastatic breast cancer", section on 'Special considerations' and "Contralateral prophylactic mastectomy" and "Breast cancer in men".)

Ovarian cancer – (See "Risk-reducing salpingo-oophorectomy in patients at high risk of epithelial ovarian and fallopian tube cancer" and "Management of ovarian cancer associated with BRCA and other genetic mutations".)

Prostate cancer – (See "Genetic risk factors for prostate cancer".)

Pancreatic cancer – (See "Familial risk factors for pancreatic cancer and screening of high-risk patients".)

Family communication

Facing Our Risk of Cancer Empowered (FORCE)

Booklet [7]

Worksheet [8]

Locating a genetics expert

Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

Genetic counselors – National Society of Genetic Counselors (NSGC)

National Institutes of Health (NIH) Cancer Genetics Services Directory

  1. Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
  2. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17:405.
  3. Mighton C, Charames GS, Wang M, et al. Variant classification changes over time in BRCA1 and BRCA2. Genet Med 2019; 21:2248.
  4. Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017; 317:2402.
  5. Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic, version 2.2023. NCCN clinical practice guidelines in oncology. Available at: https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf (Accessed on January 18, 2023).
  6. Hartmann LC, Lindor NM. The Role of Risk-Reducing Surgery in Hereditary Breast and Ovarian Cancer. N Engl J Med 2016; 374:454.
  7. The Genes Between Us: Your guide to sharing genetic test results with relatives. Facing Our Risk of Cancer Empowered (FORCE). https://www.facingourrisk.org/uploads/FORCE-TellingFamilies-5.5x8.5-200914-F_nobleeds.pdf (Accessed on May 03, 2022).
  8. Worksheet for Sharing Cancer Information with the Family. Facing Our Risk of Cancer Empowered (FORCE). Available at: https://www.facingourrisk.org/uploads/Sharing%20Worksheet%20May%202020.pdf (Accessed on May 03, 2022).
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