BRCA1 And BRCA2: Cancer Risks And Management (PDQ®): Genetics - Health Professional Information [NCI]

Genetics

Germline pathogenic variants in BRCA1/BRCA2 are associated with ovarian cancer, fallopian tube cancer, primary peritoneal cancer, male breast cancer, prostate cancer, pancreatic cancer, and early-onset breast cancer. BRCA1/BRCA2-associated cancer risks are inherited in an autosomal dominant manner.

Prevalence ofBRCA1/2Pathogenic Variants

Several studies have assessed the frequency of BRCA1 or BRCA2 pathogenic variants in women with breast or ovarian cancers.[1,2] Approximately 1 in 400 to 1 in 800 individuals in the general population (excluding those with Ashkenazi Jewish [AJ] ancestry) may carry a germline pathogenic variant in BRCA1 or BRCA2.[3,4,5]

Among the general population, the likelihood of having any BRCA pathogenic variant is as follows:

• Women with breast cancer (at any age): 1 in 50 (2%).[6]
• Women with breast cancer (younger than age 40 y): 1 in 10 (10%).[2,7,8]
• Men with breast cancer (at any age): 1 in 20 (5%).[9]
• Women with ovarian cancer (at any age): 1 in 8 to 1 in 10 (10%–15%).[10,11,12]

BRCA1/2 pathogenic variants are not currently associated with genetic anticipation, despite suggestive findings from a few studies.[13,14,15]

BRCA1/2founder pathogenic variants

The same pathogenic variant can be found in multiple unrelated families due to the founder effect (a pathogenic variant identified in a contemporary population that can be traced to a small group of founders isolated by geographic, cultural, or other factors). The presence of these founder pathogenic variants have practical implications for genetic testing.

Founder pathogenic variants have been observed in multiple population groups. In individuals with AJ ancestry, two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 pathogenic variant (6174delT) are common. However, nonfounder BRCA pathogenic variants have also been reported at a rate of 3% to 15% in the AJ population.[16,17,18]

Among AJ individuals, the likelihood of having a BRCA pathogenic variant is as follows:

• General AJ population: 1 in 40 (1.1%–2.5%).[19,20,21]
• Women with breast cancer (at any age): 1 in 10 (10%).[22]
• Women with breast cancer (younger than age 40 y): 1 in 3 (30%–35%).[22,23,24]
• Men with breast cancer (at any age): 1 in 5 (19%).[25]
• Women with ovarian cancer or primary peritoneal cancer (at any age): 1 in 3 (36%–41%).[26,27,28]

Some laboratories offer testing for ethnic-specific variants (particularly the three AJ founder variants). However, searching only for the AJ founder variants increases the risk of receiving a false-negative genetic test result (i.e., missing a nonfounder BRCA1/2 pathogenic variant or a pathogenic variant in another cancer susceptibility gene).[16,17,18]

Founder pathogenic variants have been observed in other non-AJ racial and ethnic groups, such as groups of Icelandic, Hispanic, West African, French Canadian, Polish, Sephardic Jewish, and Bahamian descent.[29,30,31,32,33,34,35,36]

BRCA1/2de novo pathogenic variant rate

The spontaneous pathogenic variant rate (de novo pathogenic variant rate) in the BRCA genes is thought to be 5% or less, based on data from limited studies.[37,38,39,40,41,42,43,44,45] However, these estimates of spontaneous pathogenic variant rates in the BRCA genes seem to overlap with the estimates of nonpaternity rates in various populations (0.6%–3.3%),[46,47,48] making the de novo pathogenic variant rate for these genes relatively low.

Detection ofBRCA1/2Variants

Variant-screening methods have differing sensitivities. Large genomic alterations such as translocations, inversions, deletions, or insertions are missed by most variant-screening techniques, including direct DNA sequencing. However, testing for these alterations is commercially available. Such rearrangements may be responsible for 12% to 18% of BRCA1 inactivating variants but are seen less frequently in the BRCA2 gene and in individuals of AJ descent.[49,50,51,52,53,54,55] Furthermore, studies have suggested that these rearrangements may be seen more frequently in Hispanic and Caribbean populations.[30,53,55]

Indications forBRCA1/2Genetic Testing

Several professional organizations and expert panels, including the American Society of Clinical Oncology,[56] the National Comprehensive Cancer Network,[57] the American Society of Human Genetics,[58] the American College of Medical Genetics and Genomics,[59] the National Society of Genetic Counselors,[59] the U.S. Preventive Services Task Force,[60] and the Society of Gynecologic Oncologists,[61] have developed clinical criteria and practice guidelines that can help health care providers identify individuals who may have a BRCA1 or BRCA2 pathogenic variant. For more information, see the Indications for hereditary breast and gynecologic cancers genetic testing section in Genetics of Breast and Gynecologic Cancers. For more information about models that can be used to estimate an individual's chance of carrying a BRCA1 or BRCA2 pathogenic variant, see the Models for Predicting the Likelihood of a BRCA1/BRCA2 Pathogenic Variant section in Genetics of Breast and Gynecologic Cancers.

Related Conditions

Fanconi anemia, a rare inherited condition, may be associated with biallelic pathogenic variants in some breast cancer susceptibility genes, including BRCA2. For more information, see the Fanconi anemia genes section in Genetics of Breast and Gynecologic Cancers.

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