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BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Synonym: HBOC

, MS, , MD, PhD, and , MD.

Author Information

Initial Posting: ; Last Update: December 15, 2016.

Summary

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.

Diagnosis

Suggestive Findings

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

  • 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.

Probability Models for BRCA1/2 Pathogenic Variants

Several models have been developed to estimate the likelihood that an individual or family has a germline pathogenic variant in BRCA1 or BRCA2 [Parmigiani et al 1998, Frank et al 2002, Antoniou et al 2004, Evans et al 2004, Tyrer et al 2004]. According to the American Society of Clinical Oncology (ASCO) policy statement on genetic testing for cancer susceptibility [American Society of Clinical Oncology 2003], there is no numeric threshold generated from these models that should be used in determining the appropriateness of genetic testing. The use of probability models, however, has been shown to help further discriminate which individuals are more likely to have a BRCA1 or BRCA2 pathogenic variant, even among experienced providers [Euhus et al 2002, de la Hoya et al 2003]. For more information about probability models for BRCA1/2 pathogenic variants, click here.

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 multi-gene 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 multi-gene 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 multi-gene 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 over time. (2) Some multi-gene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multi-gene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting secondary findings. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests.

Table 1.

Molecular Genetic Testing Used in BRCA1 and BRCA2 Associated Hereditary Breast/Ovarian Cancer (HBOC)

Gene 1Proportion of BRCA1/BRCA2 Associated HBOC Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
BRCA166%>80% 5~10% 5
BRCA234%>80% 5~10% 5
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.

The majority of pathogenic variants (≥80%) in BRCA1 and BRCA2 are detected through full gene sequencing, with an additional 10% detected through deletion/duplication analysis, which may vary across different populations [Palma et al 2008, Ewald et al 2009, Kang et al 2010, Judkins et al 2012].

Clinical Characteristics

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.

Table 2.

Risk of Malignancy in Individuals with a Germline BRCA1 or BRCA2-Pathogenic Variant.

Cancer TypeGeneral Population RiskRisk for Malignancy 1
BRCA1BRCA2
Breast12%46%-87%%38%-84%
Second primary breast2% within 5 years21.1% within 10 yrs
83% by age 70
10.8% within 10 yrs
62% by age 70
Ovarian1%-2%39%-63%16.5%-27%
Male breast0.1%1.2%Up to 8.9%%
Prostate6% through age 698.6% by age 6515% by age 65
20% lifetime
Pancreatic0.50%1%-3%2%-7%
Melanoma (cutaneous & ocular)1.6%Elevated Risk

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 BRCA2-affected families 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 et al [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 [The 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]

Differential Diagnosis

Syndromic breast cancer. Individuals with the following cancer susceptibility syndromes and/or genes have an elevated breast cancer risk. In many instances, BRCA1 and BRCA2 HBOC can be distinguished from these other disorders based on the constellation of tumors present in the family; however, in some cases, molecular genetic testing may be necessary to differentiate.

Table 3.

Disorders to Consider in the Differential Diagnosis of BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer

Cancer Susceptibility Syndrome / GeneGene(s)MOILifetime Breast Cancer Risk & Other Associated CancersOther Distinguishing Features
Li-Fraumeni syndromeTP53ADBreast cancer ≤79% 1
(often pre-menopausal)
Soft tissue sarcoma
Osteosarcoma
Brain tumors
Adrenocortical carcinoma
Leukemias
Cancers often occur in childhood or young adulthood.
Survivors are at increased risk for multiple primary cancers.
Cowden syndrome
(see PTEN Hamartoma Tumor Syndrome)
PTENADBreast cancer 25%-50%, may be ≤85% 2
Thyroid cancer
Renal cell carcinoma
Endometrial carcinoma
Colorectal cancer
Multiple hamartomas, macrocephaly, trichilemmomas, papillomatous papules
Affected individuals usually present by late 20s
Hereditary diffuse gastric cancerCDH1ADBreast cancer 39%-52% 3
(lobular breast cancer)
Diffuse gastric cancer
Majority of cancers occur before age 40 years
CHEK2
(OMIM)
CHEK2ADBreast cancer 25%-39% 4
Prostate cancer 5
Stomach cancer 5
Sarcoma 5
Kidney cancer 5
ATM heterozygotes
(see Ataxia-Telangiectasia)
ATMADBreast cancer 17%-52% 6
Other cancers
PALB2
(OMIM)
PALB2ADBreast cancer ≤58% 7
Male breast cancer 8
Pancreatic cancer 9
Peutz-Jeghers syndromeSTK11 1ADBreast cancer 32%-54%
Gastrointestinal malignancies
Ovarian (mostly SCTAT)
Cervical cancer (adenoma malignum)
Uterine cancer
Pancreatic cancer
Sertoli cell testicular cancer
Lung cancer
Gastrointestinal polyposis, mucocutaneous pigmentation, hyperpigmented macules on the fingers
Bloom’s syndromeBLMARBreast cancer risk increased 10
Epithelial carcinoma
Lymphoma
Leukemia
Other cancers
Severe pre- & postnatal growth deficiency, sparse subcutaneous fat tissue, short stature, sun-sensitive, erythematous skin lesion of the face
Werner syndromeWRNARBreast cancer risk increased 11
Sarcomas
Melanoma
Thyroid cancer
Hematologic malignancies
Characterized by the appearance, usually in the 20s, of features associated with normal aging
RAD51C
(OMIM)
RAD51COvarian cancerBreast cancer risk unknown
Lynch syndromeMLH1
MSH2
MSH6
PMS2
EPCAM
ADOvarian cancer 12
Nonpolyposis colorectal cancer
Endometrial cancer
Other cancers
It is currently unknown whether Lynch syndrome is associated with an increased risk for breast cancer. 13

RR = relative risk

SCTAT = sex cord tumor with annular tubules

1.
2.

Lifetime breast cancer risk is estimated at between 25% and 50% among women with Cowden syndrome [Hobert & Eng 2009]. Other studies have reported risks as high as 85% [Tan et al 2012, Bubien et al 2013, Ngeow et al 2014, Nieuwenhuis et al 2014]; however, there are concerns regarding selection bias in these studies.

3.
4.

CHEK2 variant c.1100delC (NM_007194​.3) associated with estimated two- to threefold increase in breast cancer risk in women and a tenfold increase of risk in men [CHEK2 Breast Cancer Case-Control Consortium 2004, Bernstein et al 2006, Weischer et al 2007]

5.

Associated with CHEK2 founder alleles: c.1100delC, c.319+1G>A(IVS2+1G>A), p.Ile157Thr (NM_007194​.3) [Näslund-Koch et al 2016]

6.

The cancer risk to individuals heterozygous for ATM disease-causing variants is approximately four times that of the general population, primarily because of an increased risk for breast cancer [Renwick et al 2006, Tavtigian et al 2009, Goldgar et al 2011, Roberts et al 2012]. Some specific pathogenic ATM variants may cause an even higher female breast cancer risk (≤52%-69%).

7.
8.

Male breast cancer has also been observed in families with molecularly confirmed PALB2-associated breast cancer [Casadei et al 2011, Ding et al 2011].

9.

Germline pathogenic variants in PALB2 have been identified in families with multiple cases of pancreatic cancer, but the exact risk for pancreatic cancer conferred by germline variants in PALB2 has not yet been established [Jones et al 2009, Slater et al 2010].

10.

Sixteen individuals with breast cancer, of 207 individuals with Bloom’s syndrome reported in Bloom’s Syndrome Registry

11.

Seven of 248 neoplasms reported in individuals with Werner syndrome [Lauper et al 2013]

12.

Lifetime risks of ovarian cancer in Lynch syndrome range from 4% to 12%. Unlike ovarian cancer associated with germline pathogenic variants in BRCA1/2, those associated with Lynch syndrome are more likely to be endometrioid or clear cell [Ketabi et al 2011].

13.

Breast cancer has been reported in families with Lynch syndrome, but consistent associations have not been demonstrated [Gruber & Petersen 2002, Müller et al 2002, Walsh et al 2010].

Management

Evaluations Following Initial Diagnosis

Individuals who have a germline pathogenic variant in BRCA1 or BRCA2 are counseled at the time of disclosure of molecular genetic test results about their options for Surveillance and Prevention of Primary Manifestations.

Treatment of Manifestations

National Comprehensive Cancer Network (NCCN) 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. See NCCN guidelines for the treatment of breast cancer and the treatment of other BRCA1- and BRCA2-associated malignancies (registration required).

Prevention of Primary Manifestations

Breast cancer

  • Consider prophylactic bilateral mastectomy
  • Given the conflicting data on the degree of risk reduction of breast cancer associated with prophylactic oophorectomy, consider discussing the risks and benefits of this approach with a genetics specialist.
  • Chemoprevention. In a retrospective study tamoxifen reduced the risk for breast cancer by 62% among healthy women with a BRCA2 germline variant [King et al 2001]. The sample size, however, was extremely small. In a nested case-control study, tamoxifen use was associated with a 41%-50% reduction in the risk of developing contralateral breast cancer [Narod et al 2000, Metcalfe et al 2005]. There have been no prospective randomized trials of tamoxifen as a chemoprevention agent in women with BRCA1/2 pathogenic variants.
  • Breast feeding for a cumulative total of more than one year reduced the risk for breast cancer [Jernstrom et al 2004].

Ovarian cancer/fallopian tube cancer

  • Consider prophylactic oophorectomy, recognizing that completion of childbearing may factor into this decision. Several studies have documented a significant (80%-96%) risk reduction in ovarian cancer following risk-reducing oophorectomy [Kauff et al 2002, Rebbeck et al 2002, Rutter et al 2003].
  • Salpingectomy. Recent advances in understanding the molecular events preceding ovarian cancer have established the fallopian tube as the origin of the majority of high-grade serous ovarian cancers, leading to the consideration of salpingectomy with ovarian retention until the age of natural menopause as the first step in primary prevention. This approach is likely to reduce the health hazards of premature menopause, but its adoption will require prospective data to establish its safety and efficacy [Daly et al 2015].
  • Tubal ligation. A meta-analysis of 13 studies showed a reduction in risk for ovarian cancer of 34% in the general population after tubal ligation [Cibula et al 2011]. A meta-analysis of modifiers of risk of cancer in individuals with pathogenic variants in BRCA1/2 found a reduction in the risk of ovarian cancer in females with a BRCA1 pathogenic variant, although study design issues limit the impact of these findings [Friebel et al 2014].
  • Oral contraceptive use has been associated with a reduction in ovarian cancer risk of 14% among women who had ever used oral contraceptives and 38% among long-term users [Whittemore et al 2004a].
    Note: There is no evidence that use of current (after 1975) oral contraceptive formulations increases the risk for early-onset breast cancer for women with a germline BRCA1 or BRCA2 pathogenic variant.

Prevention of Secondary Complications

Significant adverse consequences of tamoxifen treatment included higher rates of endometrial cancer and thromboembolic episodes (including pulmonary embolism) in those individuals who took the medication than in those who did not. Women with a history of thromboembolic disease or with a coagulation disorder should avoid taking tamoxifen. Women on tamoxifen should be counseled to report any abnormal vaginal bleeding immediately to their gynecologist.

Surveillance

Women

  • Monthly breast self-examination
  • Clinical breast examination every 6-12 months beginning at age 25
  • Annual breast MRI beginning at age 25, or individualized based on family history if a breast cancer diagnosis before age 30 is present
  • Annual mammogram beginning at age 30
  • Annual transvaginal ultrasound and serum CA-125 concentration beginning at age 35 years (or individualized based on the earliest age of onset in the family) may be considered for those women who have not elected to undergo prophylactic oophorectomy.
    Note: Annual pelvic ultrasound and/or CA-125 concentration has not been effective in detecting early-stage ovarian cancer, either in high-risk or average-risk women.

Men

  • Breast self-examination training and regular monthly breast self-examination beginning at age 35
  • Annual clinical breast examination beginning at age 35
  • Annual prostate cancer screening beginning at age 45

Women and men

  • Screening for melanoma should be individualized based on the family history.
  • Screening of asymptomatic individuals for pancreatic cancer is not generally recommended, but is possible in research settings.

Agents/Circumstances to Avoid

No data specific to individuals with BRCA1/2 pathogenic variants are available.

Evaluation of Relatives at Risk

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

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several studies currently underway are looking at novel approaches to the treatment of BRCA-associated breast and ovarian cancer. The majority of the studies involve PARP inhibitors, and have led to FDA approval for one of these agents in treatment of recurrent ovarian cancer. Newer studies are exploring the use of PARP inhibitors in other BRCA-associated cancers (e.g., pancreatic cancer). Given the experimental data showing increased sensitivity of BRCA cell lines to platinum-based agents, there is interest in platinum-based regimens for breast cancer in the neoadjuvant, adjuvant, and metastatic setting.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Hormone replacement therapy (HRT). General population studies suggest that long-term estrogen replacement therapy in postmenopausal women may increase breast cancer risk, but that short-term use to treat menopausal symptoms does not. However, even relatively short-term combined estrogen plus progestin use was shown to increase the incidence of breast cancers in a randomized, placebo control trial of HRT [Chlebowski et al 2003].

Three observational studies on the impact of HRT on breast cancer risk in BRCA 1/2 heterozygotes have been published. Rebbeck et al [2005] evaluated breast cancer risk associated with HRT after bilateral prophylactic oophorectomy in a cohort of 462 women with a BRCA1 or BRCA2 germline pathogenic variant and found that HRT of any type after bilateral prophylactic oophorectomy did not significantly alter the reduction in breast cancer risk associated with the surgery. The postoperative follow up was 3.6 years. It was concluded that short-term HRT does not substantially increase the risk for breast cancer in women with a BRCA1 or BRCA2 germline pathogenic variant. A subsequent study of expanded data from this cohort included 1299 women with a mean follow-up of 5.4 years. There was no increase in breast cancer risk, and a significant decrease in breast cancer risk was found among BRCA1 heterozygotes [Domchek et al 2011]. In another matched case-control study of 472 postmenopausal women with a BRCA1 pathogenic variant, the use of HRT was associated with a reduction in breast cancer risk [Eisen et al 2008]. Finally, a case-control study of 432 matched pairs with a mean follow up of 4.3 years also found a decrease in the risk for breast cancer in BRCA1 heterozygotes [Kotsopoulos et al 2016]. Taken together, these studies support the short-term use of HRT among BRCA1/2 heterozygotes who have undergone surgical menopause.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

BRCA1 and BRCA2 hereditary breast and ovarian cancer syndrome (HBOC) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband with a BRCA1/2 pathogenic variant

Sibs of a proband with a BRCA1/2 pathogenic variant

  • The risk to full sibs of the proband depends on the genetic status of the proband's parents: the risk that a sib of an index case will inherit the BRCA1 or BRCA2 germline pathogenic variant is 50% if one parent has the BRCA1 or BRCA2 germline variant.
  • The risk of developing cancer, however, depends on numerous variables including the penetrance of the pathogenic variant and the gender and age of the individual.

Offspring of a proband with a BRCA1/2 pathogenic variant. The offspring of an individual identified as having a BRCA1 or BRCA2 germline pathogenic variant have a 50% chance of inheriting the variant. The risk of developing cancer, however, depends on numerous variables including the penetrance of the pathogenic variant and the gender and age of the individual.

Other family members of a proband with a BRCA1/2 pathogenic variant. The risk to other family members depends on the status of the proband's parents. If a parent has a BRCA1 or BRCA2 germline variant, his or her family members are at risk. Their exact risk depends on their position in the pedigree.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo (although rare, de novo variants in both BRCA1 and BRCA2 have been reported). However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for the determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ®, National Cancer Institute).

At-risk asymptomatic adult relatives. In general, relatives of an individual who has a BRCA1 or BRCA2 germline pathogenic variant should be counseled regarding their risk of having inherited the same variant, their options for molecular genetic testing, their cancer risk, and recommendations for cancer screening (see Surveillance) and prophylactic surgery (see Prevention of Primary Manifestations).

At-risk adult relatives who have not inherited the cancer-predisposing germline variant identified in the proband are presumed to be at or above the general population risk of developing cancer, depending on personal risk factors. For example, a female at-risk relative who does not have the family-specific BRCA1 or BRCA2 pathogenic variant may still be at an elevated risk for breast cancer based on a breast biopsy history that revealed atypical ductal hyperplasia.

For family members determined to be at general population risk of developing cancer, appropriate cancer screening such as that recommended by the American Cancer Society or the National Comprehensive Cancer Network (NCCN) for individuals of average risk is recommended. Note: This presumption cannot apply to individuals who did not have an identifiable BRCA1 or BRCA2 germline pathogenic variant if the affected individual in the family either has not undergone molecular genetic testing of BRCA1 or BRCA2 or did not have an identified BRCA1 or BRCA2 pathogenic variant.

Testing of asymptomatic individuals younger than age 18 years. In general, genetic testing for HBOC is not recommended for at-risk individuals younger than age 18 years. Guidelines established jointly by the American College of Medical Genetics and the American Society of Human Genetics state that predictive genetic testing should only be performed in individuals younger than age 18 years when it will affect their medical management. Management for HBOC-related cancer is typically recommended to begin at approximately age 25, which is why it is recommended that the decision to test be postponed until an individual reaches adulthood and can make an independent decision. It is important to note, however, that since there are rare reported cases of individuals with HBOC diagnosed with cancer at very young ages, it is recommended that screening be individualized based on the earliest diagnosis in the family.

For more information, see also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the BRCA1 or BRCA2 germline pathogenic variant has been identified in the family, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for HBOC are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Breast Cancer Information Core
    Breast cancer resources
    National Human Genome Research Institute (NHGRI)
  • Bright Pink
    670 North Clark Street
    Suite 2
    Chicago IL 60654
  • FORCE: Facing Our Risk of Cancer Empowered
    A discussion forum specifically for women who are at a high risk of developing ovarian cancer or breast cancer
    16057 Tampa Palms Boulevard West
    PMB #373
    Tampa FL 33647
    Phone: 866-288-7475 (toll-free)
    Fax: 954-827-2200
    Email: info@facingourrisk.org
  • Gilda's Club Worldwide
    48 Wall Street
    11th Floor
    New York NY 10005
    Phone: 888-445-3248 (toll-free)
    Fax: 917-305-0549
    Email: info@gildasclub.org
  • My46 Trait Profile
  • National Breast and Ovarian Cancer Centre (NBOCC)
    Locked Bag 3
    Strawberry Hills New South Wales 2012
    Australia
    Phone: +61 2 9357 9400
    Fax: +61 2 9357 9477
    Email: directorate@nbocc.org.au
  • National Breast Cancer Coalition (NBCC)
    An advocacy group seeking public policy change to benefit breast cancer patients and survivors
    1101 17th Street Northwest
    Suite 1300
    Washington DC 20036
    Phone: 800-622-2838 (toll-free); 202-296-7477
    Fax: 202-265-6854
    Email: info@stopbreastcancer.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Ovarian Cancer Coalition (NOCC)
    2501 Oak Lawn Avenue
    Suite 435
    Dallas TX 75219
    Phone: 888-682-7426 (Toll-free Helpline); 214-273-4200
    Fax: 214-273-4201
    Email: nocc@ovarian.org
  • NCBI Genes and Disease
  • Probability of Breast Cancer in American Women
    National Cancer Institute Public Inquiries Office
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • Sharsheret
    Linking young Jewish women in their fight against breast cancer
    1086 Teaneck Road
    Suite 3A
    Teaneck NJ 07666
    Phone: 866-474-2774 (toll-free); 201-833-2341
    Email: info@sharsheret.org
  • Susan G. Komen Breast Cancer Foundation
    Information, referrals to treatment centers. Answers questions from recently diagnosed women and provides emotional support. Funds research programs for women who do not have adequate medical service and support.
    5005 LBJ Freeway
    Suite 250
    Dallas TX 75244
    Phone: 877-465-6636 (Toll-free Helpline)
    Fax: 972-855-1605
    Email: helpline@komen.org
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
  • CancerCare
    275 Seventh Avenue
    Floor 22
    New York NY 10001
    Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
    Fax: 212-712-8495
    Email: info@cancercare.org
  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
    Email: cancergovstaff@mail.nih.gov
  • National Coalition for Cancer Survivorship (NCCS)
    A consumer organization that advocates on behalf of all people with cancer
    1010 Wayne Avenue
    Suite 770
    Silver Spring MD 20910
    Phone: 888-650-9127 (toll-free); 301-650-9127
    Fax: 301-565-9670
    Email: info@canceradvocacy.org
  • Familial Ovarian Cancer Registry
    Roswell Park Cancer Institute
    Elm and Carlton Streets
    Buffalo NY 14263
    Phone: 716-845-4503
  • Prospective Registry of MultiPlex Testing (PROMPT)
    PROMPT is an online research registry for patients and families who have undergone multiplex genetic testing and were found to have a genetic variation which may be linked to an increased risk of having cancer.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B.

OMIM Entries for BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer (View All in OMIM)

113705BREAST CANCER 1 GENE; BRCA1
114480BREAST CANCER
600185BRCA2 GENE; BRCA2
604370BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1; BROVCA1
612555BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 2; BROVCA2

BRCA1

Gene structure. BRCA1 spans more than 80 kb of genomic DNA and encodes a 7.8-kb transcript composed of 24 coding exons [Miki et al 1994, Deng 2006]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 1800 pathogenic variants have been identified in BRCA1. While a small number of these variants have been identified repeatedly in unrelated families, the vast majority have not been reported in more than a few families. Overall, among individuals undergoing molecular genetic testing of BRCA1 and BRCA2, approximately 2.9% will have a variant of uncertain clinical significance [Eggington et al 2012] – a proportion that has declined significantly over the past ten years. (For more information, see Table A.)

Reduced-penetrance variant. p.Arg1699Gln is established to be a reduced penetrance variant in BRCA1 [Spurdle et al 2012]. Data from functional assays were ambiguous for deficiency across multiple assays. Thus, this allele was determined to be associated with intermediate risk for breast and ovarian cancer, highlighting challenges for risk modeling and clinical management of individuals of this and other potential moderate-risk variants.

Table 4.

Selected BRCA1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.68_69delAG
(185delAG or 187delAG)
p.Glu23ValfsTer17NM_007294​.3
NP_009225​.1
c.5096G>Ap.Arg1699Gln
c.5266dupC
(5385insC or 5382insC)
p.Gln1756ProfsTer74

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. BRCA1 codes for a 220-kd protein of 1863 amino acids. The breast cancer type 1 susceptibility protein (BRCA1) is a phosphoprotein normally located in the nucleus [Chen et al 1996]. Its functional domains include:

  • A RING finger domain near the N-terminus; may facilitate both protein-protein (BRCA1 / BARD1) and protein-DNA interactions [Boddy et al 1994]
  • Two nuclear localization signals located in exon 11
  • An "SQ" cluster between p.1280 and p.1524
  • A BRCT domain at the C-terminus

BRCA1 interacts with several proteins involved in cellular pathways, including cell-cycle progression, gene transcription regulation, DNA damage response, and ubiquitination [Deng 2006, Rosen et al 2006].

The BRCA1/BARD1 protein complex enhances ubiquitin ligase activity, which is associated with the regulation of centrosome function and involved in DNA repair and cell cycle regulation [Sankaran et al 2006, Bork et al 1997, Callebaut & Mornon 1997].

BRCA1 is expressed in most tissues and cell types analyzed, suggesting that it is not the gene expression pattern that leads to the tissue-restricted phenotype of breast and ovarian cancer. The transcription of BRCA1 is induced late in the G1 phase of the cell cycle and remains elevated during the S phase, indicating some role in DNA synthesis [Gudas et al 1996, Rajan et al 1996]. A variety of evidence now points to the breast cancer type 1 susceptibility protein as being directly involved in the DNA repair process.

BRCA1 colocalizes with BRCA2 and RAD51 at sites of DNA damage and activates RAD51-mediated homologous recombination repair of DNA double-strand breaks [Cousineau et al 2005]. One of the targets of BRCA1 transcriptional activation appears to be the p21 cyclin-dependent kinase inhibitor, itself a potent suppressor of growth at the G1/S checkpoint [Somasundaram et al 1997, Ouchi et al 1998].

Complete loss of Brca1 in the mouse is embryonic lethal, characterized by a lack of cell proliferation [Hakem et al 1996, Ludwig et al 1997]. Cells derived from mouse embryos lacking Brca1 are defective in their repair of DNA damage [Gowen et al 1998]. Interestingly, Brca1 knockout mice can be partially rescued by crossing with a Tp53 knockout strain, suggesting that these genes interact with the TP53-mediated DNA damage checkpoint [Brugarolas & Jacks 1997]. Therefore, the available evidence indicates that BRCA1 serves as a "caretaker," like TP53, helping to maintain genomic integrity [Zhang et al 1998].

Abnormal gene product. Most BRCA1 pathogenic variants lead to frameshifts resulting in a missing or non-functional protein. In cancers from individuals with a BRCA1 germline pathogenic variant, the normal allele is deleted or inactivated, resulting in somatic inactivation of BRCA1. This strongly suggests that BRCA1 is a tumor-suppressor gene whose loss of function can result in genomic instability, resulting in a high susceptibility to malignant transformation [Smith et al 1992, Deng 2006]. Additional evidence in support of a tumor suppressor function is that overexpression of the BRCA1 protein leads to growth suppression similar to that seen with the classic tumor suppressors TP53 and the retinoblastoma gene (RB1) [Holt et al 1996]. Loss of function of BRCA1 results in defects in DNA repair, defects in transcription, abnormal centrosome duplication, defective G2/M cell-cycle checkpoint regulation, impaired spindle checkpoint, and chromosome damage [Brodie & Deng 2001, Deng 2002, Venkitaraman 2002].

BRCA2

Gene structure. BRCA2 encodes a 10.4-kb transcript composed of 27 exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. As with BRCA1, more than 1800 pathogenic variants in BRCA2 have been identified. (For more information, see Table A.) Overall, approximately 2.9% of individuals undergoing molecular genetic testing of BRCA1 and BRCA2 will have a variant of uncertain clinical significance [Eggington et al 2012] – a proportion that has declined significantly over the past ten years (see NHGRI-BIC Database). In the future, some of these will likely prove to be benign variants without clinical significance, while others may be associated with an increased cancer risk.

Reduced-penetrance variant. There is evidence that p.Lys3326Ter is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2, although penetrance is reduced. This was demonstrated through a large case-control study based on an international consortium of patients with cancer. Further studies are needed to determine the biologic mechanism of action responsible for these associations [Meeks et al 2015].

Table 5.

Selected BRCA2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.771_775delTCAAA
(999del5)
p.Asn257LysfsTer17NM_000059​.3
NP_000050​.2
c.5946delT
(6174delT)
p.Ser1982ArgfsTer22
c.9976A>Tp.Lys3326Ter

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

Normal gene product. BRCA2 encodes a 380-kd protein of 3,418 amino acids. Eight 30-40 residue motifs found in exon 11 mediate the binding of breast cancer type 2 susceptibility protein (BRCA2) to RAD51. BRCA2 is a phosphoprotein normally located in the nucleus [Bertwistle et al 1997]. BRCA2 protein has no recognizable protein motifs and no apparent relation to the breast cancer type 1 susceptibility protein.

Like BRCA1, BRCA2 is expressed in most tissues and cell types analyzed, indicating that gene expression does not account for the tissue-restricted phenotype of breast and ovarian cancer. BRCA2 transcription is induced late in the G1 phase of the cell cycle and remains elevated during the S phase, indicating some role in DNA synthesis [Rajan et al 1996, Vaughn et al 1996].

BRCA2 appears to be involved in the DNA repair process. The breast cancer type 2 susceptibility protein interacts with the RAD51 protein, a key component in homologous recombination and double-strand break repair [Sharan et al 1997, Wong et al 1997]. Through this interaction, BRCA2 regulates the availability and activity of RAD51, which coats single-strand DNA to form a nucleoprotein filament that invades and pairs with a homologous DNA duplex to initiate strand exchange [Venkitaraman 2002].

Complete loss of Brca2 in the mouse is embryonic lethal, characterized by a lack of cell proliferation [Ludwig et al 1997, Sharan et al 1997, Suzuki et al 1997]. Cells derived from mouse embryos lacking Brca2 are defective in their repair of DNA damage [Connor et al 1997, Chen et al 1998b] and are hypersensitive to radiation and radiomimetics [Abbott et al 1998, Biggs & Bradley 1998, Chen et al 1998a, Morimatsu et al 1998] – findings that may have implications for both mammographic screening and treatment modalities. Finally, Brca2 knockout mice can be partially rescued by crossing with a Tp53 knockout strain, suggesting that these genes interact with the TP53 -mediated DNA damage checkpoint [Brugarolas & Jacks 1997]. Therefore, the available evidence indicates that BRCA2 is a "caretaker," like TP53, serving to maintain genomic integrity [Zhang et al 1998]. It is likely that BRCA2 will eventually be implicated in a variety of cellular processes, only some of which will be related to their role in the etiology of breast and ovarian cancer.

Abnormal gene product. Most BRCA2 pathogenic variants reported to date consist of frameshift deletions, insertions, or nonsense variants that predict premature truncation of protein transcription, consistent with the loss of function that is expected with clinically significant variants of tumor suppressor genes. Cells lacking BRCA2 are deficient in the repair of double-strand DNA breaks, as reflected in a hypersensitivity to ionizing radiation [Venkitaraman 2001].

References

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online; registration or institutional access required. 2010. Accessed 12-8-16.
  2. Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 12-8-16. [PubMed: 23428972]
  3. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 12-8-16.

Literature Cited

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Suggested Reading

  1. Boughey JC, Hartmann LC, Anderson SS, Degnim AC, Vierkant RA, Reynolds CA, Frost MH, Pankratz VS. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol. 2010;28:3591–6. [PMC free article: PMC2917314] [PubMed: 20606088]
  2. Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. 2005;23:276–92. [PubMed: 15637391]
  3. Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol. 2005;23:1656–63. [PubMed: 15755973]
  4. National Cancer Institute. Genetics of breast and gynecologic cancers (PDQ®). Bethesda, MD: National Cancer Institute. Available online. 2013. Accessed 12-13-16.

Chapter Notes

Author History

Julie O Bars Culver, MS; Fred Hutchinson Cancer Research Center (1998-2011)
Wylie Burke, MD, PhD; University of Washington (1998-2005)
Mary B Daly, MD, PhD (1998-present)
Gerald L Feldman, MD, PhD; Wayne State University School of Medicine (2002-2016)
Judith L Hull, MS; Memorial Sloan-Kettering Cancer Center (1998-2005)
Ephrat Levy-Lahad, MD; Sharre Zedek Medical Center (1998-2007)
Tuya Pal, MD (2016-present)
Nancie Petrucelli, MS (2002-present)

Revision History

  • 15 December 2016 (sw) Comprehensive update posted live
  • 26 September 2013 (me) Comprehensive update posted live
  • 20 January 2011 (me) Comprehensive update posted live
  • 19 June 2007 (me) Comprehensive update posted to live Web site
  • 5 December 2005 (cd) Revision: Differential Diagnosis
  • 3 September 2004 (jbc) Revision: Genetically Related Disorders
  • 29 March 2004 (ca) Comprehensive update posted to live Web site
  • 4 March 2000 (me) Comprehensive update posted to live Web site
  • 4 September 1998 (pb) Review posted to live Web site
  • January 1998 (jbc) Original submission
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Bookshelf ID: NBK1247PMID: 20301425

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