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FOR THE TESTED INDIVIDUAL – This information is intended to assist your physician or other qualified health care professional as part of their comprehensive assessment of the best approach to managing your genetic test results. It is not specific advice for your care and it does not replace consultation with a qualified health care professional. You should not alter your medical care based on this report without speaking to, and receiving guidance from, your physician based on your specific case.
FOR THE CLINICIAN – This information was prepared on the date indicated on the file and may have been updated subsequently. Please check UpToDate (UpToDate.com) for the latest version of this and other gene test interpretation monographs. UpToDate subscribers can access these monographs by entering the gene name or the phrase "Gene test interpretation" into the UpToDate search box. Your use of this information is subject to the terms set forth at https://www.uptodate.com/legal/license and any other terms in any applicable license agreement. This information is no substitute for individual patient assessment based on the healthcare provider's evaluation of each patient that includes personal and family history, findings from the physical examination, laboratory and other testing, and other factors unique to the patient. The information should be used as a tool to help the clinician reach diagnostic and treatment decisions, bearing in mind that individual and unique circumstances may lead to decisions other than those presented. The opinions expressed are those of the monograph's authors and editors.
Supported by an unrestricted educational grant from AncestryHealth®.
- Beth N Peshkin, MS, CGC
- Claudine Isaacs, MD
- Section Editors:
- Harold J Burstein, MD, PhD
- Anne Slavotinek, MBBS, PhD
- Deputy Editors:
- Jennifer S Tirnauer, MD
- Sadhna R Vora, MD
- Diane MF Savarese, MD
INTRODUCTION — This monograph summarizes the interpretation of germline testing of the 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 in the clinical care of the individual who was tested. These subjects are discussed separately . (See 'UpToDate topics' below.)
How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).
Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).
●Genotype – Identifies the variants in the gene(s) tested. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected cancer syndrome).
●Interpretation – Determines pathogenicity of the variants identified. May require updating. (See 'Classification of variants' below.)
The table provides a glossary of genetic testing terms (table 2).
Classification of variants — Some tests use comprehensive sequencing, whereas others only screen for selected variants such as the Ashkenazi Jewish founder mutations in BRCA1 (185delAG [also called 187delAG or c.68_69delAG] and 5382insC [also called 5385insC or c.5266dupC]) and/or BRCA2 (c.5946delT [also called 6174delT]).
The classification for many variants continues to be updated, especially for variants of uncertain significance (VUS), as more evidence becomes available . The uncertainty reflects the available research rather than the accuracy of genotyping or the likelihood of disease.
If there is concern about the classification, such as for a VUS or low-penetrance variant, obtain an updated interpretation periodically (eg, annually). 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 require a request. Many VUSs are reclassified as benign. Likely benign and benign variants are not reported (or are reported as negative).
Disease associations — Pathogenic and likely pathogenic variants in BRCA1 and BRCA2 are associated with increased risk for several cancers (table 4). This is referred to as a hereditary breast and ovarian cancer syndrome .
BRCA1- or BRCA2-associated hereditary breast and ovarian cancer 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 the 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 all variants in BRCA1 and BRCA2 that are pathogenic or likely pathogenic the same for purposes of counseling and cancer risk reduction, regardless of the initial reason for testing and the family history.
Discussion should include the range of cancer risks (table 4), possible interventions for surveillance or risk reduction (table 5), and implications for at-risk family members (see 'At-risk relatives' below). The discussion of risks is individualized based on the person's age.
Counseling may require additional visits or referral to a genetic counselor, clinical geneticist, or oncologist. Acting upon genetic test results is usually not an emergency; the individual can be reassured that 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 . The type of cancer and age of onset in a family member may also inform screening (eg, screening at an earlier age if a family member has an earlier age of onset).
Several evaluations and interventions can reduce the risk of BRCA1 and BRCA2-associated cancers (table 5). Use of these strategies depends on the patient's age, values and preferences, and, for women, desire for childbearing (algorithm 1).
•Increased surveillance if mastectomy has not been performed:
-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 .
•Hormonal chemoprevention may be offered if prophylactic bilateral mastectomy has not been performed; however, data are very limited.
•Increased surveillance with breast self-examination and annual clinical breast examination starting at age 35.
●Ovarian and other gynecologic cancers:
•Discussion of risk-reducing bilateral salpingo-oophorectomy (rrBSO) at age 35 to 40 for BRCA1 carriers and age 40 to 45 for BRCA2 carriers, in both cases after completion of childbearing and with shared decision-making . (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Risk-reducing surgery'.)
•Possible increased surveillance, including transvaginal ultrasound and CA-125 for women 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 .
•Discussion of hormone replacement therapy for the management of menopausal symptoms.
•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'.)
•Discussion of screening for those with a family history of pancreatic cancer. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients".)
•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 uveal (ocular) melanoma. (See "Cancer risks and management of BRCA1/2 carriers without cancer", section on 'Screening for other cancers'.)
Additional details and the supporting evidence are discussed separately. (See "Cancer risks and management of BRCA1/2 carriers without cancer" and "Genetic counseling: Family history interpretation and risk assessment" and 'UpToDate topics' below.)
Implications of a negative test — Negative testing means no pathogenic variants were identified (algorithm 1). However, some tests only query a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes.
●If the familial variant in BRCA1 or BRCA2 is known and the tested individual does not have that variant, usually they can be reassured that they are not at high risk for BRCA-associated cancers, with the caveats outlined above (see 'How to read the report' above). However, it is important to assess family history and other cancer-risk factors to provide an individualized risk.
●If a familial variant in BRCA1 or BRCA2 is not known and results of genetic testing are negative, additional risk factors (genetic or acquired) may be present, and additional testing (for other variants in BRCA1 or BRCA2, or with a cancer gene panel) and/or surveillance is based on family history and other risk factors. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong family history of cancer. (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).
New information may become available, and 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 — The implications of genetic test results should be discussed with the individual's oncologist or surgeon; in some cases, referral to a specialist in hereditary breast and ovarian cancer may be appropriate.
BRCA1-associated breast cancers are often triple-negative (negative for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2]; seen in one-half to three-fourths of cases).
The presence of a pathogenic or likely pathogenic variant in BRCA1 or BRCA2 may impact several aspects of management, including the following:
●More extensive breast cancer surgery (eg, bilateral mastectomy to reduce the risk of additional breast cancers).
●Incorporation of a poly-ADP-ribose polymerase (PARP) inhibitor into systemic therapy for several cancer types.
●Risk stratification for prostate cancer.
●Additional surveillance and prophylactic measures. (See 'Implications of a pathogenic or likely pathogenic variant' above.)
Counseling and testing of family members is also often appropriate. (See 'Considerations for the family' below.)
Further discussion of management of BRCA1 and BRCA2-associated cancers is presented separately. (See 'UpToDate topics' 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. The need for additional testing may be discussed with a genetic counselor, the primary oncologist, or other specialists with expertise in managing hereditary breast and ovarian cancer. (See 'Locating a genetics expert' below.)
CONSIDERATIONS FOR THE FAMILY
Preconception 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 conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Couples 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 having inherited the variant is 50 percent for first-degree relatives. 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.
●Most of the associated cancers do not develop until adulthood. Testing may be deferred until age 18 to allow for informed consent. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
●BRCA genes and associated cancers:
•Cancer risks – (See "Cancer risks and management of BRCA1/2 carriers without cancer".)
•Breast cancer – (See "Factors that modify breast cancer risk in women" and "ER/PR negative, HER2-negative (triple-negative) breast cancer" and "Systemic treatment for metastatic breast cancer: General principles", section on 'PARP inhibition for BRCA carriers' and "Contralateral prophylactic mastectomy" and "Breast cancer in men".)
•Ovarian cancer – (See "Risk-reducing salpingo-oophorectomy in women 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".)
•Variant classification – (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic testing – (See "Genetic testing".)
•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
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
- Supporting references are provided in the associated UpToDate topics, with selected citation(s) below.
- 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.
- Mighton C, Charames GS, Wang M, et al. Variant classification changes over time in BRCA1 and BRCA2. Genet Med 2019; 21:2248.
- 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.
- https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf (Accessed on January 07, 2020).
- Hartmann LC, Lindor NM. The Role of Risk-Reducing Surgery in Hereditary Breast and Ovarian Cancer. N Engl J Med 2016; 374:454.
|Section of the report||Action(s)||Concern(s)|
||Individuals may inadvertently provide the wrong name on a test sample. Testing should be done by a laboratory that can ensure that the identification matches the tested individual.|
||All actionable medical testing (eg, positive finding or negative finding in an individual suspected of having a genetic disorder) should be conducted in a CLIA-certified laboratory that has met appropriate quality standards for performing the specific test. Some direct-to-consumer testing is not performed in CLIA-certified laboratories and may lack appropriate quality controls.|
|Date of testing||
||Germline variants do not change over time. However, as new data become available, the classification of variant pathogenicity may change, especially for variants classified as VUS. Repeat testing may be considered, as the technologies for exome sequencing may improve and may identify a variant missed on a prior test.|
||Not all genetic testing panels are comprehensive in the genes or variants in those genes they evaluate. New disease genes or clinically important variants in existing genes may be identified through further research.|
||Not all methods will identify all variants. In some cases such as HFE testing, only one or two variants are clinically relevant, and sequencing of the entire coding region of the gene is not required, whereas in other conditions, limited testing for one or two variants may miss clinically important findings. Gene panels may be especially useful when multiple genes could potentially be responsible for a clinical phenotype.|
|Classification of pathogenicity||
||Interpretation of pathogenicity takes into account many data sources including laboratory research, research databases, population studies, and pedigree analyses. In some cases, pathogenicity is well established (eg, the variant that causes sickle cell disease); in others, it is more subjective and incomplete. Variants classified as VUS, likely benign, or benign generally are not actionable and should not impact medical interventions. Consulting a publicly curated database such as ClinVar or discussing the results with an expert in the specific disease, or referral to a clinical geneticist, genetic counselor, or disease expert may be helpful.|
* Indications for testing vary according to the individual's medical history, family history, and other factors such as desire for preconception counseling. In some cases, an individual who did not have a clinical indication for testing may have an unexpected finding from genetic testing that, if accurate, would indicate the need for an intervention, and such findings may be actionable regardless of the initial reasons for testing.
|Autosomal dominant||Pattern of inheritance that requires only one affected variant allele (a variant inherited from one parent or that arises de novo) to transmit the trait or risk of disease. Not sex-linked. First-degree relatives (siblings, children) have a 50% chance of sharing (or inheriting) the variant allele.|
|Autosomal recessive||Pattern of inheritance that generally requires both variants on both alleles (one from each parent) in order to transmit the trait or risk of disease. Not sex-linked. Individuals with one variant are sometimes called carriers.|
|Carrier||Individual who has a specific variant in one allele of the gene in their germline DNA (inherited from one parent or arising de novo). For recessive disorders, refers to a heterozygote who is generally (or mostly) unaffected. For dominant disorders, carriers are generally considered at risk for the disorder.|
|Expressivity||Differences in the severity of disease manifestations in individuals who share the same genotype (eg, cystic fibrosis is said to have variable expressivity because two individuals with the same genotype may have differences in the degree of pancreatic or lung dysfunction).|
|Genotyping||Determining the DNA sequence of a particular gene or portion of a gene in an individual. Can be done on DNA from sources such as nucleated epithelial cells from saliva, tumor cells from a biopsy, or WBCs from peripheral blood. Can be used to determine germline or somatic sequence, depending on the source of the cells.|
|Germline||Derived from the gametes (sperm or egg cells) and present in the early embryo; germline variants are typically present in all body cells and do not change. Germline variants can be passed down to subsequent generations.|
|Mutation||Term that may be used to describe changes in DNA or protein sequence compared with a reference sequence. The American College of Genetics and Genomics (ACMG) has expressed concern that this term can cause confusion or incorrect assumptions regarding pathogenicity, and the ACMG recommends that findings from genetic testing be described using the term "variant" with a qualifier regarding pathogenicity (or lack thereof).|
|Pathogenicity||Likelihood that a specific variant is capable of causing disease or conferring disease risk. Does not determine the likelihood that disease will occur (which depends on other factors such as disease penetrance). Refer to separate table in UpToDate for the categories.|
|Pedigree||Diagram of a family showing relationships among family members, sex of each family member, presence or absence of one or more genetic disorders, and often the age at which they manifested. Used in genetic counseling to identify possible inherited causes of disease and their inheritance patterns.|
|Penetrance||Likelihood that a person with a disease-associated variant will manifest one or more features of the disease. Many disease variants have incomplete or variable penetrance, meaning that not all individuals with the variant will manifest the associated disorder.|
|Somatic||Referring to tissues that are not within the germline. Variation that arises in somatic tissues is not passed from parent to offspring. Somatic mutations are common in cancer.|
|Variant||Change in the sequence of DNA compared with a reference sequence. Variants can be benign (associated with normal gene function), pathogenic (associated with altered gene function and/or clinical disease, also called mutations), or somewhere in between. The term polymorphism is often (but not exclusively) used for benign variants. Refer to a separate table in UpToDate that defines the categories.|
|VUS||Variant of uncertain significance (or unknown significance). Refers to a variant for which insufficient information is available to classify as benign or pathogenic.|
|Pathogenic||Associated with disease risk|
|Likely pathogenic||>90% likelihood of disease risk association|
|Variant of uncertain significance (VUS)||Available data do not allow classification into one of the other categories|
|Likely benign||>90% likelihood that variant is not associated with disease risk|
|Benign||Not associated with disease risk|
- Population data (allele frequency; prevalence of variant in affected individuals versus controls)
- Computational data (predicted effect on protein sequence or function)
- Functional data (functional studies show or do not show deleterious effect)
- Segregation data (variant segregates with disorder in families)
Supported by an unrestricted educational grant from AncestryHealth®.
|Cancer type||Risk in carriers to age 70 years*||Lifetime risk in general population¶||Comments|
BRCA1: 55 to 70%BRCA2: 45 to 70%
In most studies, lifetime risk in BRCA1 carriers is higher than that observed in BRCA2 carriers.The incidence of breast cancer diagnosed younger than 50 years of age is higher in BRCA1 carriers compared with BRCA2 carriers, but both groups have an increased risk of premenopausal breast cancer.
|Contralateral (opposite) breast (women)||Up to 63% at 25 years postdiagnosis but highly dependent on age at diagnosis of first breast cancer||~7% at 25 years postdiagnosis||
Risk is affected by other factors such as tamoxifen use and oophorectomy.Mutation carriers who have had lumpectomy have increased ipsilateral risks over long follow-up periods.
BRCA1: Approximately 40%BRCA2: Approximately 15%
The incidence of ovarian cancer diagnosed younger than 50 years of age is higher in BRCA1 carriers and overall rare in all carriers younger than 40 years old.Risk of fallopian tube cancer is also substantially elevated.
BRCA1: Approximately 15 to 20%BRCA2: Approximately 30 to 40%
~14% Whites~19% African Americans
|Risk appears to be higher in BRCA2 carriers and in men younger than 65 years old.|
BRCA1: 1%BRCA2: 8%
|0.1%||Risk before age 50 is very low.|
BRCA1: 2 to 4%BRCA2: 5%
|Colon||Not well defined||~5%||Studies have not been consistent about whether risk is elevated. If elevated, risk is likely to be small.|
|Melanoma||Not well defined||
~0.1% African Americans
|Possible increases in skin and ocular melanoma, particularly for BRCA2 carriers.[5-7]|
|Other sites||Not well defined||Varied||These sites may include cancer of the stomach and uterine serous carcinoma.|
* Risk to individuals over age 70 is higher, but data are generally unavailable.
¶ Lifetime risk at birth for all races unless otherwise specified.
- SEER Cancer Statistics Review, 1975-2011. Available online at http://seer.cancer.gov/csr/1975_2011/ (Accessed on July 17, 2019).
- New malignancies among cancer survivors: SEER Cancer Registries, 1973-2000. Available online at http://seer.cancer.gov/archive/publications/mpmono/ (Accessed on July 17, 2019).
- Key statistics for breast cancer in men: American Cancer Society. Available online at http://www.cancer.org/cancer/breastcancerinmen/detailedguide/breast-cancer-in-men-key-statistics (Accessed on July 17, 2019).
- Melanoma statistics. Melanoma Research Alliance. Available online at https://www.curemelanoma.org/about-melanoma/melanoma-statistics-2 (Accessed on November 1, 2019).
- Gumaste PV, Penn LA, Cymerman RM, et al. Skin cancer risk in BRCA1/2 mutation carriers. Br J Dermatol 2015; 172: 1498-1506.
- Mersch J, Jackson MA, Park M. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer 2015; 121: 269-75.
- Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91: 1310-6.
|Patient population||Intervention(s) that may be appropriate|
|First- and second-degree relatives||
|Ovarian or other gynecologic cancer||
* Ensure that the genetic testing is performed properly, the patient identification is correct, and the interpretation of pathogenicity is accurate based on the most recent data analysis.
¶ Pathogenic and likely pathogenic variants are treated the same for purposes of surveillance and risk-reduction interventions; these interventions are independent of family history.
Δ VUSs lack sufficient information from clinical and bench research to be classified as pathogenic or benign. Continue to seek updated interpretation of pathogenicity periodically (eg, annually).
◊ Refer to UpToDate for the age at which interventions are initiated (eg, delay of rrBSO until after childbearing), the frequency at which they are performed, and the supporting evidence.
Contributor DisclosuresBeth N Peshkin, MS, CGCNothing to discloseClaudine Isaacs, MDGrant/Research/Clinical Trial Support: Tesaro [Breast/ovarian cancer]. Consultant/Advisory Boards: Pfizer [Breast/ovarian cancer]; Pfizer [Breast cancer/Endocrine therapy in premenopausal]; Novartis [Breast cancer/Endocrine therapy in premenopausal]; AstraZeneca [Breast/ovarian cancer]; AstraZeneca [Breast cancer/Endocrine therapy in premenopausal]. Speaker's Bureau: Pfizer [Breast cancer/Endocrine therapy in premenopausal].Harold J Burstein, MD, PhDNothing to discloseAnne Slavotinek, MBBS, PhDGrant/Research/Clinical Trial Support: UCSF [P3EGS project]; National Human Genome Research Institute, National Institutes of Health [Clinical sequencing evidence generating research 2]; Retrophin [CTX, early-onset idiopathic bilateral cataracts (Natural history study testing for cerebrotendinous xanthomatosis)]. Consultant/Advisory Boards: American Board of Medical Genetics and Genomics [Director]; Roche [Alpha globin testing]. Employment: American Journal of Medical Genetics [Deputy Editor]. Other Financial Interest: Oxford University Press [Royalties from book].Jennifer S Tirnauer, MDNothing to discloseSadhna R Vora, MDNothing to discloseDiane MF Savarese, MDNothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.