Clinical characteristics.

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for female and male breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. The exact cancer risks differ slightly depending on whether HBOC is caused by a BRCA1 or BRCA2 pathogenic variant.

Diagnosis/testing.

The diagnosis of BRCA1 and BRCA2 HBOC is established in a proband by identification of a heterozygous germline pathogenic variant in BRCA1 or BRCA2 on molecular genetic testing.

Management.

Treatment of manifestations: National Comprehensive Cancer Network guidelines suggest that women with a BRCA1/2 pathogenic variant could consider bilateral mastectomy as a primary surgical treatment of breast cancer because of their elevated rate of ipsilateral and contralateral breast cancer. Treatment of ovarian and other cancers in individuals with a BRCA1/2 pathogenic variant is similar to that for sporadic cancers.

Prevention of primary manifestations: Prophylactic bilateral mastectomy, prophylactic oophorectomy, and chemoprevention (e.g., tamoxifen) have been used for breast cancer prevention, but have not been assessed by randomized trials in high-risk women. Prophylactic oophorectomy for ovarian cancer prevention.

Surveillance: Breast cancer screening in women relies on a combination of monthly breast self-examination, annual or semiannual clinical breast examination, annual mammography, and breast MRI. Annual transvaginal ultrasound and CA-125 concentration beginning at age 35 years may be considered for ovarian cancer screening. However, this screening has not been effective in detecting early-stage ovarian cancer, either in high-risk or average-risk women. For men, breast cancer screening includes breast self-examination education and training and annual clinical breast examination beginning at age 35. Annual prostate cancer screening should begin at age 45. Screening for melanoma should be individualized based on the family history. Screening of asymptomatic individuals for pancreatic cancer is not generally recommended.

Evaluation of relatives at risk: Once a cancer-predisposing BRCA1 or BRCA2 germline pathogenic variant has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial pathogenic variant and thus need increased surveillance and early intervention when a cancer is identified.

Genetic counseling.

Germline pathogenic variants in BRCA1 and BRCA2 are inherited in an autosomal dominant manner. The vast majority of individuals with a BRCA1 or BRCA2 pathogenic variant have inherited it from a parent. However, because of incomplete penetrance, variable age of cancer development, cancer risk reduction resulting from prophylactic surgery, or early death, not all individuals with a BRCA1 or BRCA2 pathogenic variant have a parent affected with cancer.

Offspring of an individual with a BRCA1 or BRCA2 germline pathogenic variant have a 50% chance of inheriting the variant. Prenatal testing is possible for pregnancies at increased risk if the cancer-predisposing variant in the family is known; however, requests for prenatal diagnosis of adult-onset diseases are uncommon and require careful genetic counseling.

Suggestive Findings

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) should be suspected in individuals with a personal or family history (1^st-, 2^nd-, or 3^rd-degree relative in either lineage) of any of the following characteristics [NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian]:

• Breast cancer diagnosed at or before age 50 years
• Ovarian cancer
• Multiple primary breast cancers either in one or both breasts
• Male breast cancer
• Triple-negative (estrogen receptor-negative, progesterone receptor-negative, and HER2/neu [human epidermal growth factor receptor 2]-negative) breast cancer, particularly when diagnosed before age 60 years
• The combination of pancreatic cancer and/or prostate cancer (Gleason score ≥7) with breast cancer, and/or ovarian cancer
• Breast cancer diagnosed at any age in an individual of Ashkenazi Jewish ancestry
• Two or more relatives with breast cancer, one under age 50
• Three or more relatives with breast cancer at any age
• A previously identified BRCA1 or BRCA2 pathogenic variant in the family

Notes: (1) "Breast cancer" includes both invasive cancer and ductal carcinoma in situ (DCIS). (2) "Ovarian cancer" includes epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer.

Establishing the Diagnosis

The diagnosis of BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is established in a proband by identification of a heterozygous germline pathogenic variant in BRCA1 or BRCA2 on molecular genetic testing (see Table 1).

Note: (1) Molecular testing is most likely to be informative in an individual with a BRCA1/2-associated cancer (e.g., breast cancer at age <50 years, ovarian cancer) and is often referred to as the "best test candidate." Thus, molecular genetic testing ideally should be performed initially on the "best test candidate" as opposed to a family member who may have an unrelated cancer or who may not have a personal history of cancer. (2) If the "best test candidate" is not available, molecular testing may be performed on another individual, without a cancer history, with the understanding that failure to detect a pathogenic variant does not eliminate the possibility of a BRCA1 or BRCA2 pathogenic variant being present in the family.

Molecular testing approaches can include a BRCA1 and BRCA2 gene panel and use of a multigene panel:

• BRCA1 and BRCA2 gene panel. Sequence analysis of BRCA1 and BRCA2 is performed concurrently with deletion/duplication analysis.
  Targeted analysis can be considered in individuals of Ashkenazi Jewish ancestry by starting with targeted testing for three BRCA1 and BRCA2 pathogenic founder variants: BRCA1 c.68_69delAG (BIC: 185delAG) BRCA1 c.5266dupC (BIC: 5382insC), and BRCA2 c.5946delT (BIC: 6174delT), which together account for up to 99% of pathogenic variants identified in individuals of Ashkenazi Jewish ancestry. If no pathogenic variant is identified by targeted analysis, it may be appropriate to proceed with sequence and deletion/duplication analyses of BRCA1 and BRCA2 or a multigene panel.
  Note: In a family known to have a BRCA1 or BRCA2 germline pathogenic variant, at-risk adults may be tested for the family-specific germline pathogenic variant. In most cases, relatives at risk need only be tested for the family-specific germline pathogenic variant, except in the following situations:
  • Individuals of Ashkenazi Jewish heritage should consider testing for all three founder germline pathogenic variants because of the high population frequency of these founder pathogenic variants as well as reports of the coexistence of more than one founder germline pathogenic variant in some families.
  • Individuals with a familial BRCA1 or BRACA2 pathogenic variant on one side of the family and characteristics of HBOC on the other side of the family may consider sequence analysis and deletion/duplication analysis of BRCA1 and BRCA2, which would (1) detect the familial germline pathogenic variant if present and also (2) address whether a germline pathogenic variant is present on the other side of the family.
• A multigene panel that includes BRCA1 and BRCA2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk for male and female breast cancer, ovarian cancer (includes fallopian tube and primary peritoneal cancers), and to a lesser extent other cancers such as prostate cancer, pancreatic cancer, and melanoma primarily in individuals with a BRCA2 pathogenic variant. Estimates of malignancy risk vary considerably depending on the context in which they were derived. The following is a summary of the risk for malignancy in an individual with a germline BRCA1 or BRCA2 pathogenic variant.

Breast cancer. Breast cancer is the most common malignancy in individuals with a germline BRCA1 or BRCA2 pathogenic variant with a lifetime risk ranging from 46% to 87%.

The first estimates of breast cancer risk associated with BRCA1 pathogenic variants was based on 33 families with evidence of linkage to BRCA1 with an estimated cumulative risk of 87% by age 70 years [Ford et al 1994]. For BRCA2, early cumulative breast cancer risk estimates reached 84% by age 70 years [Ford et al 1998]. Subsequent studies have revealed lower risk estimates. In a US study that included 676 Ashkenazi families and 1272 families of other ethnicities, Chen et al [2006] estimated the cumulative breast cancer risk in women with a germline BRCA1 pathogenic variant to age 70 years at 46%. Satagopan et al [2001] studied incident breast cancer cases among Ashkenazi Jewish women and found the penetrance of breast cancer at age 80 years among BRCA1 heterozygotes to be 59% (95% CI = 40%-93%) and among BRCA2 heterozygotes to be 38% (95% CI = 20%-68%). More recently, in a cohort of 978 individuals with a BRCA1 pathogenic variant and 909 individuals with a BRCA2 pathogenic variant from the United Kingdom, Mavaddat et al [2013] estimated the average cumulative breast cancer risks by age 70 in BRCA1 heterozygotes to be 60% and 55% for BRCA2 heterozygotes (see Table 2).

A total of 16 studies comprising 10,180 individuals were recently analyzed to determine overall survival among those with BRCA1/2 pathogenic variants [Templeton et al 2016]. The pooled analysis showed no association between the presence of germline BRCA1/2 pathogenic variants and overall survival (HR 1.06, 95% CI 0.84-1.34, p=0.61). The findings were similar when the influence of BRCA1 and BRCA2 pathogenic variants were evaluated on overall survival independently (BRCA1: HR 1.20, 95% CI 0.89-1.61, p=0.24; BRCA2: HR 1.01, 95% CI 0.80-1.27, p = 0.95). There, however, appears to be a strong and statistically significant association between estrogen receptor (ER) expression and overall survival in individuals with germline BRCA1 pathogenic variants but not with age or progesterone receptor (PR) expression.

BRCA1-related tumors show an excess of medullary histopathology, are of higher histologic grade, are more likely than sporadic tumors to be estrogen receptor-negative and progesterone receptor-negative, and are less likely to demonstrate HER2/neu overexpression; thus, BRCA1-related tumors fall within the category of "triple-negative" breast cancer [Rakha et al 2008, Lee et al 2011] and overlap with basal-like breast cancers. Several reports have also suggested a link between germline BRCA2 pathogenic variants and triple-negative breast cancer. In studies of persons with triple-negative breast cancer, the incidence of germline BRCA2 pathogenic variants ranges from 3% to 17% [Evans et al 2011, Meyer et al 2012, Couch et al 2015]. The evidence that a germline BRCA1/2 pathogenic variant is associated with poor survival outcomes for breast cancer has been inconsistent [Verhoog et al 2000, Bordeleau et al 2010, van den Broek et al 2015, Zhong et al 2015].

Contralateral breast cancer (CBC). Several studies have reported higher rates of CBC [Graeser et al 2009, Malone et al 2010, Pierce et al 2010, van der Kolk et al 2010, Metcalfe et al 2011a, Vichapat et al 2012, van den Broek et al 2015] in women treated conservatively. Predictors of CBC include age at first breast cancer, family history of early-onset breast cancer, and the affected BRCA gene [Graeser et al 2009, Malone et al 2010, Metcalfe et al 2011a, van den Broek et al 2015]. The risk for CBC was decreased among women who had undergone prophylactic oophorectomy [Metcalfe et al 2011a]. In an unselected cohort of individuals with breast cancer, ten-year cumulative contralateral breast cancer risks of 21.1% for those with BRCA1 pathogenic variants and 10.8% for those with BRCA2 pathogenic variants were found.

Using a cohort of 978 BRCA1 and 909 BRCA2 heterozygotes from the United Kingdom, Mavaddat et al estimated the cumulative risk of contralateral breast cancer to be 83% in BRCA1 heterozygotes and 62% for BRCA2 heterozygotes by age 70 [Mavaddat et al 2013].

Ipsilateral breast cancer. Two case-control studies reported significantly higher rates of ipsilateral breast cancer in individuals with a germline BRCA1/2 pathogenic variant compared with sporadic controls [Haffty et al 2002, Seynaeve et al 2004], however, other studies have not found an increased risk for ipsilateral breast cancer in those with germline BRCA1/2 pathogenic variants when compared with women who had sporadic breast cancer [Robson et al 2004, Graeser et al 2009] and also demonstrated a significant ipsilateral breast cancer risk reduction in individuals receiving radiation therapy compared with those who were not receiving radiation therapy [Metcalfe et al 2011b].

Ovarian cancer (including fallopian tube and primary peritoneal cancers). BRCA germline pathogenic variants confer an excessive risk for ovarian cancer ranging from 16.5% to 63%. The first estimates of ovarian cancer risk associated with BRCA1 pathogenic variants were as high as 63% by age 70 [Easton et al 1995] and for BRCA2 pathogenic variants were as high as 27% by age 70 [Ford et al 1998]. Subsequent studies have revealed lower risk estimates. In the US population study that included 676 Ashkenazi families and 1272 families of other ethnicities, Chen et al [2006] estimated ovarian cancer risk to age 70 years in individuals with a germline BRCA1 pathogenic variant at 39% (95% CI = 0.30%-0.50%). Satagopan et al [2002] found the estimated penetrance of ovarian cancer at age 70 years among BRCA1 heterozygotes to be 37% (95% CI = 25%-71%) and among BRCA2 heterozygotes to be 21% (95% CI = 13%-41%). More recently, in a cohort of 978 BRCA1 and 909 BRCA2 heterozygotes from the United Kingdom, Mavaddat et al [2013] estimated the average cumulative risks by age 70 in BRCA1 heterozygotes to be 59% for ovarian cancer and 16.5% for BRCA2 heterozygotes (see Table 2).

An excess of serous adenocarcinomas have been observed in women with germline BRCA1 or BRCA2 pathogenic variants [McLaughlin et al 2013]. Serous adenocarcinomas are generally of higher grade and exhibit prominent intraepithelial lymphocytes, marked nuclear atypia, and abundant mitoses [Fujiwara et al 2012]. Given recent advances in the understanding of the molecular pathways of ovarian cancer, it has been concluded that most cases of high-grade serous cancers arise from the fallopian tubes rather than the ovaries [Daly et al 2015].

Studies on ovarian cancer survival in women with a germline BRCA1/2 pathogenic variant have yielded conflicting results. A pooled analysis of 26 observational studies found a more favorable survival rate among individuals with a detectable BRCA1 or BRCA2 pathogenic variant compared to individuals without a BRCA1/2 pathogenic variant, (BRCA1 HR 0.78, 95% CI 0.68-0.89; BRCA2 HR 0.61, 95% CI 0.50-0.76). These results persisted when controlling for stage, grade, histology, and age at diagnosis [Bolton et al 2012]. A large population-based case-control study found a higher response to platinum-based therapy, longer progression-free survival, and improved overall survival among individuals with a germline BRCA1/2 pathogenic variant [Alsop et al 2012]. Similarly, individuals with platinum-sensitive epithelial ovarian tumors were more likely to have germline BRCA1/2 pathogenic variants than individuals with platinum-resistant tumors [Dann et al 2012]. More recently, in a large series of unselected individuals with ovarian cancer, the short-term survival of individuals with ovarian cancer with germline BRCA1/2 pathogenic variants was better than that of individuals without an identified BRCA1/2 pathogenic variant, however, the survival advantage was short lived and did not lead to a long-term survival benefit [McLaughlin et al 2013].

Male breast cancer. Based on data from 1939 families with 97 male subjects with breast cancer, the risk of developing breast cancer in males with a BRCA1 or BRCA2 pathogenic variant were evaluated. The cumulative risk of breast cancer was higher in both BRCA1 and BRCA2 male heterozygotes than in males without a BRCA1/2 pathogenic variant at all ages. With respect to the relative risks of developing breast cancer, the risk was higher for men in their 30s and 40s and decreased with increasing age. When compared to BRCA1, males with BRCA2 pathogenic variants had higher relative and cumulative risks. The estimated cumulative risk of breast cancer for males with BRCA1 pathogenic variants at age 70 years was 1.2% (95% CI 0.22%-2.8%) and for males with a BRCA2 pathogenic variant was 6.8% (95% CI 3.2%-12%) [Tai et al 2007].

In the largest study of families with BRCA2 to date, using both retrospective and prospective analyses of 321 families, three breast cancers occurred in male first-degree relatives, suggesting a risk for male breast cancer to 80 years of 8.9% [Evans et al 2010] (see Table 2).

Prostate cancer. A series of 913 males with prostate cancer, ranging in age from 36 to 86 years, were screened for germline BRCA1 pathogenic variants; four pathogenic variants were identified; three of which were identified in individuals diagnosed at or before age 65 years. Based on previously estimated population frequencies of BRCA1 pathogenic variants, it was estimated that BRCA1 pathogenic variants confer a relative risk of prostate cancer of approximately 3.7-fold (95% CI 1.02-9.6), which translates to an 8.6% cumulative risk by age 65 years [Leongamornlert et al 2012].

The lifetime risk for prostate cancer in males with BRCA2 pathogenic variants has been estimated at 20% [Breast Cancer Linkage Consortium 1999]. In 2011, Kote-Jarai et al screened 1864 males with prostate cancer diagnosed between age 36 and 88 years for BRCA2 pathogenic variants. Nineteen protein-truncating variants were identified, all of which occurred in individuals who were diagnosed with prostate cancer at or before age 65 years. Based on previously estimated frequencies of BRCA2 pathogenic variants, it was estimated that BRCA2 pathogenic variants confer an increased relative risk of prostate cancer of approximately 8.6-fold (95% CI 5.1-12.6) by age 65 years corresponding to an absolute risk of approximately 15% by age 65 years [Kote-Jarai et al 2011]. In addition, BRCA2-related prostate cancer has been associated with a higher histologic grade [Gallagher et al 2010] and results in a poorer overall survival [Thorne et al 2011] (see Table 2).

Pancreatic cancer. An increased risk for pancreatic (adenocarcinoma) cancer has been associated with pathogenic variants in BRCA1 and BRCA2. In the cross-sectional study of the Breast Cancer Linkage Consortium [1999], Thompson & Easton [2002] reported a significant increase in the risk for pancreatic cancer in those with germline BRCA1 pathogenic variants (RR=2.26, 95% CI=1.26-4.06, P=0.004) and in those with BRCA2 pathogenic variants (RR=3.51, 95% CI=1.87-6.58, P=0.0012). Risch et al [2006] estimated the risk of pancreatic cancer among relatives of females with invasive ovarian cancer in 1171 unselected females with ovarian cancer in Ontario. The relative risk for pancreatic cancer was 3.1 (95% CI=0.45-21) in relatives of those with BRCA1 pathogenic variants and 6.6% (95% CI=1.9-23) in relatives of those with BRCA2 pathogenic variants, compared to relatives of those without pathogenic variants. More recently, a prospective study of 5149 females with BRCA1 or BRCA2 pathogenic variants showed a statistically significant 2.4-fold increase in the incidence of pancreatic cancer and – unlike in previous studies – the increase in the incidence of pancreatic cancer was similar for BRCA1 (SIR=2.55) and BRCA2 (SIR=2.13) [Iqbal et al 2012] (see Table 2).

Melanoma. Although it is less well studied, the literature suggests that melanoma risk, both cutaneous and ocular, may be elevated in some but not all families with a BRCA2 pathogenic variant [Breast Cancer Linkage Consortium 1999, Hearle et al 2003, van Asperen et al 2005]. An analysis of 490 families with BRCA1/2 pathogenic variants showed an increased risk for ocular melanoma in individuals with germline BRCA2 pathogenic variants (RR=99.4, 95%CI=11.1-359.8) [Moran et al 2012] (see Table 2).

Other cancers. In addition to the above-mentioned cancers, individuals with BRCA1 and BRCA2 pathogenic variants may be at a higher risk for additional malignancies based on family-based studies as well as case-control studies [Breast Cancer Linkage Consortium 1999, Thompson et al 2001, van Asperen et al 2005], although the absolute risks for these other cancers are small. The Breast Cancer Linkage Consortium reported an increased relative risk for cancers of the uterine body and cervix, with relative risks of 2.6 and 3.7, in women younger than age 65 years with a germline BRCA1 pathogenic variant [Thompson & Easton 2002]. The Netherlands Collaborative Group on Hereditary Breast Cancer reported statistically increased relative risks for cancers of the gallbladder and bile duct, with relative risks of 3.5 and 5.0, respectively [van Asperen et al 2005]. It is important to note, however, that in some of these studies, diagnoses were not consistently confirmed by pathology and therefore, excess risk of cervix and uterus as well as gallbladder and bile duct cancers may represent misclassifications of ovarian and pancreatic cancers, respectively. Furthermore, data suggesting a causative link between endometrial cancer and pathogenic variants of BRCA1/2 may be related to tamoxifen exposure [Beiner et al 2007] rather than the presence of a pathogenic variant, as previous studies have found that uterine papillary serous cancer does not appear to be a manifestation of HBOC [Goshen et al 2000]. Finally, initial reports of increased colorectal cancer risk have generally not been replicated [Gruber & Petersen 2002, Niell et al 2004].

No associated benign tumors or physical abnormalities are presently known to be associated with pathogenic variants in BRCA1 or BRCA2.

Phenotype Correlations by Gene

Ovarian cancer and primary papillary serous carcinoma of the peritoneum are considerably more common and tend to develop at an earlier age in women with a germline BRCA1 pathogenic variant as compared to women with a germline BRCA2 pathogenic variant [Casey et al 2005, Yates et al 2011]. However, those with BRCA2 pathogenic variants tend to be at greater risk for male breast cancer, prostate cancer, pancreatic cancer, and melanoma.

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been identified in families with BRCA1 and BRCA2 pathogenic variants. Such correlations are not currently used in individual risk assessment and management, but may be in future with appropriate validation.

Families with protein-truncating BRCA1 pathogenic variants from the Breast Cancer Linkage Consortium reported breast cancer risk to be lower with pathogenic variants in the central region of the gene (nucleotides 2,401-4,190) compared with surrounding regions. Furthermore, ovarian cancer risk was associated with a lower risk with pathogenic variants 3’ to nucleotide 4,191 [Thompson et al 2001].

Studies in the Ashkenazi Jewish population have also found higher rates of ovarian cancer in individuals with the c.68_69delAG (BIC: 185delAG) pathogenic variant, in the 5' end of BRCA1, as compared to individuals with the c.5266dupC (BIC: 5382insC) pathogenic variant, which is in the 3' end of the gene [Lubinski et al 2004]. However, c.5266dupC pathogenic variants appear to confer a higher risk for breast cancer, including bilateral breast cancer, and both breast and ovarian cancer in the same individual when compared to both c.68_69delAG (BIC: 185delAG) in BRCA1 and c.5946delT (BIC: 6174delT) in BRCA2 [Satagopan et al 2002, Lubinski et al 2004].

An ovarian cancer cluster region (OCCR) in or near exon 11 in both BRCA1 and BRCA2 has been identified [Rebbeck et al 2015]. Pathogenic variants within the OCCR have been associated with a higher ratio of ovarian to breast cancer than is seen in families with a pathogenic variant elsewhere in the genes.

In BRCA1 and BRCA2, multiple breast cancer cluster regions (BCCR) have been observed and are associated with relatively elevated breast cancer risk and lower ovarian cancer risk [Rebbeck et al 2015].

Penetrance (Cancer Risk)

Female breast and ovarian cancers remain the most common cancers associated with BRCA1/2 pathogenic variants. Females with BRCA1/2 pathogenic variants have up to an 87% risk of developing an associated cancer, while males have up to a 20% risk.

Prevalence

BRCA1- and BRCA2-associated hereditary breast and ovarian cancer (HBOC) is the most common form of hereditary breast and ovarian cancer and occurs in all ethnic and racial populations. The prevalence of BRCA1/2 pathogenic variants in the general population (excluding Ashkenazim) is estimated at 1:400 to 1:500 [Anglian Breast Cancer Study Group 2000, Whittemore et al 2004b].

Ashkenazi Jewish. The combined frequency of the following three pathogenic variants in the Ashkenazi Jewish population is 1:40 [King et al 2003]:

• BRCA1 c.68_69delAG (BIC: 185delAG) occurs with a frequency of 1%;
• BRCA1 c.5266dupC (BIC: 5382insC) has an estimated prevalence of 0.1%-0.15%;
• BRCA2 c.5946delT (BIC: 6174delT) occurs with a frequency of about 1.52%.

[Ferla et al 2007]