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 clinical care of the tested individual. These subjects are discussed separately [1]. (See 'UpToDate topics' below.)
OVERVIEW
How to read the report — An approach to reviewing the report is summarized in the checklist (table 1). Considerations include the extent of testing, accuracy of variant identification, and interpretation:
●Extent of testing – The majority of laboratories perform comprehensive sequencing of BRCA1 and BRCA2 genes; however, others test only for selected pathogenic variants, such as one identified in a family member or Ashkenazi Jewish founder mutations in BRCA1 (185delAG [also called 187delAG or c.68_69delAG] and 5382insC [also called 5385insC or c.5266dupC]) and BRCA2 (c.5946delT [also called 6174delT]).
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 variants are seen in the general population, and compound heterozygotes have been identified unexpectedly.
●Accuracy of genotype – 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), as new research and data become available. (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 becomes available [3]. The uncertainty reflects the available research 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 and 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 male breast cancer, 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.
Rarely, biallelic pathogenic variants in BRCA2 are associated with Fanconi anemia (FA), and biallelic pathogenic variants in BRCA1 are associated with an 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), and implications for at-risk relatives (see 'At-risk relatives' 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.
•Annual mammography may be considered if gynecomastia is present, starting at age 50 or 10 years earlier than the youngest age at male breast cancer diagnosis in the family, if earlier.
●Ovarian and other gynecologic cancers:
•Recommendation for risk-reducing bilateral salpingo-oophorectomy (rrBSO), generally at age 35 to 40 for BRCA1 carriers and age 40 to 45 for BRCA2 carriers, unless the age at ovarian cancer diagnosis in the family warrants consideration at an earlier age. 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 benefit 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.
●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. (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 are not comprehensive.
●Once a familial pathogenic variant is identified 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, family history is important, including the side of the family without the variant, as well as other personal cancer risk factors, for an individualized risk assessment.
●If a familial variant is unknown and genetic testing is negative, additional risk factors (genetic or acquired) may be present, and comprehensive testing (for other variants in BRCA1 or BRCA2, or with a cancer gene panel) may be recommended. 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. (See 'Locating a genetics expert' below.)
Implications of a VUS — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (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 (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 family members are also often appropriate. (See 'Considerations for the family' 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 specialist. (See 'Locating a genetics expert' below.)
CONSIDERATIONS FOR THE FAMILY
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), or to select male embryos. 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 who test positive for 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 (male and female 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 cancer; 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. It is recommended that genetic testing be deferred until age ≥18 years to allow 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)
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
