TLTK Utbt.2

NLM Citation: Petrucelli N, Daly MB, Pal T.
BRCA1- and BRCA2-

Associated Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated
2016 Dec 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors.
GeneReviews® [Internet]. Seattle (WA): University of Washington,
Seattle; 1993-2021.
Bookshelf URL: https://www.ncbi.nlm.nih.gov/books/
BRCA1- and BRCA2-Associated Hereditary Breast and

Ovarian Cancer
Synonym: HBOC
Nancie Petrucelli, MS,1 Mary B Daly, MD, PhD,2 and Tuya Pal, MD3
Created: September 4, 1998; Updated: 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
Author Affiliations: 1 Wayne State University School of Medicine/Detroit Medical Center; Karmanos Cancer Institute,
Cancer Genetic Counseling Service, Detroit, Michigan; Email: [email protected]. 2 Chair, Department of Clinical
Genetics, Fox Chase Cancer Center, Philadelphia, Pennsylvania; Email: [email protected]. 3 Moffitt Cancer Center,
Tampa, Florida; Email: [email protected].
Copyright © 1993-2021, University of Washington, Seattle. GeneReviews is a registered trademark of the University of
Washington, Seattle. All rights reserved.
2 GeneReviews®
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 a pregnancy at increased risk if the cancer-predisposing variant in the
family is known; however, requests for prenatal testing for 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 (NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk
Assessment: Breast and Ovarian; no-fee registration and login 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.
BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer 3
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 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.
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• Amultigene panelthat 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.
Table 1. Molecular Genetic Testing Used in BRCA1 and BRCA2 Associated Hereditary Breast/Ovarian Cancer (HBOC)
Proportion of BRCA1/BRCA2- Proportion of Pathogenic Variants 2 Detected by Method

Gene 1 Associated HBOC Attributed to Gene-targeted deletion/
Pathogenic Variants in Gene Sequence analysis 3
duplication analysis 4
BRCA1 66% >80% 5 ~10% 5
BRCA2 34% >80% 5 ~10% 5
1. See Table A. Genes and Databases for chromosome locus and protein.
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. 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 used may 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 whole-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.
Risk for Malignancy 1
Cancer Type General Population Risk
BRCA1 BRCA2
Breast 12% 46%-87% 38%-84%
21.1% w/in 10 yrs; 83% by age
Second primary breast 2% w/in 5 yrs 10.8% w/in 10 yrs; 62% by age 70
70
Ovarian 1%-2% 39%-63% 16.5%-27%
Table 2. continued from previous page.
Risk for Malignancy 1

Cancer Type General Population Risk
BRCA1 BRCA2
Male breast 0.1% 1.2% Up to 8.9%
Prostate 6% through age 69 8.6% by age 65 15% by age 65; 20% lifetime
Pancreatic 0.50% 1%-3% 2%-7%
Melanoma (cutaneous &
1.6% Elevated risk
ocular)
1. Ford et al [1994], Easton et al [1995], Ford et al [1998], Robson et al [1998], Breast Cancer Linkage Consortium [1999], Verhoog et al
[2000], Satagopan et al [2002], Thompson & Easton [2002], Hearle et al [2003], Kirova et al [2005], Robson et al [2005], van Asperen et
al [2005], Chen et al [2006], Risch et al [2006], Tai et al [2007], Graeser et al [2009], Evans et al [2010], van der Kolk et al [2010], Kote-
Jarai et al [2011], Iqbal et al [2012], Leongamornlert et al [2012], Moran et al [2012], Mavaddat et al [2013], van den Broek et al [2015]
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
6 GeneReviews®
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
8 GeneReviews®
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%;
• BRCA1c.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]
Genetically Related (Allelic) Disorders

Germline pathogenic variants in BRCA2 have been associated with the following:
• Familial pancreatic cancer [Ferrone et al 2009, Iqbal et al 2012, Mocci et al 2013]
• Fanconi anemia complementation group FANCD1 [Howlett et al 2002, Stecklein & Jensen 2012]
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 / Lifetime Breast Cancer Risk & Other
Gene(s) MOI Other Distinguishing Features
Gene Associated Cancers
Breast cancer ≤79% 1 (often pre-
Cancers often occur in childhood or
menopausal), soft tissue sarcoma,
Li-Fraumeni syndrome TP53 AD young adulthood. Survivors are at ↑
osteosarcoma, brain tumors,
risk for multiple primary cancers.
adrenocortical carcinoma, leukemias
Breast cancer 25%-50% (may be Multiple hamartomas, macrocephaly,
Cowden syndrome (See PTEN ≤85%), 2 thyroid cancer, renal cell trichilemmomas, papillomatous
PTEN AD
Hamartoma Tumor Syndrome.) carcinoma, endometrial carcinoma, papules; affected persons usually
colorectal cancer present by late 20s.
Breast cancer 39%-52% 3 (lobular Majority of cancers occur before age 40
Hereditary diffuse gastric cancer CDH1 AD
breast cancer), diffuse gastric cancer yrs
Breast cancer 25%-39%, 4 prostate
CHEK2 (OMIM 604373) CHEK2 AD cancer, 5 stomach cancer, 5 sarcoma, 5
kidney cancer 5
10 GeneReviews®
Table 3. continued from previous page.
Cancer Susceptibility Syndrome / Lifetime Breast Cancer Risk & Other

Gene(s) MOI Other Distinguishing Features
Gene Associated Cancers
ATM heterozygotes (See Ataxia- Breast cancer 17%-52%, 6 other
ATM AD
Telangiectasia.) cancers
Breast cancer ≤58%, 7 male breast
PALB2 (OMIM 610355) PALB2 AD
cancer, 8 pancreatic cancer 9
Breast cancer 32%-54%,
gastrointestinal malignancies, ovarian Gastrointestinal polyposis,
(mostly SCTAT), cervical cancer mucocutaneous pigmentation,
Peutz-Jeghers syndrome STK11 1 AD
(adenoma malignum), uterine cancer, hyperpigmented macules on the
pancreatic cancer, Sertoli cell testicular fingers
cancer, lung cancer
Severe pre- & postnatal growth
Breast cancer risk ↑, 10 epithelial
deficiency, sparse subcutaneous fat
Bloom syndrome BLM AR carcinoma, lymphoma, leukemia,
tissue, short stature, sun-sensitive,
other cancers
erythematous skin lesion of the face
Breast cancer risk ↑, 11 sarcomas, Characterized by appearance (usually
Werner syndrome WRN AR melanoma, thyroid cancer, in the 20s) of features assoc w/normal
hematologic malignancies aging
RAD51C (OMIM 602774) RAD51C Ovarian cancer Breast cancer risk unknown
MLH1
MSH2 Ovarian cancer, 12 nonpolyposis It is currently unknown whether Lynch
Lynch syndrome MSH6 AD colorectal cancer, endometrial cancer, syndrome is assoc w/↑ risk for breast
PMS2 other cancers cancer. 13
EPCAM
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; RR = relative risk; SCTAT = sex cord tumor with
annular tubules; XL = X-linked
1. Ruijs et al [2010]
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. Brooks-Wilson et al [2004], Kaurah et al [2007]
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. Antoniou et al [2014]
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 syndrome reported in Bloom 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 (NCCN Guidelines; no-fee registration and login
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 [Jernström 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.
12 GeneReviews®
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 in the US and EU Clinical Trials Register in Europe for 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, mode(s) of
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; it is not meant to address all personal, cultural, or ethical issues that may arise 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
• The vast majority of individuals with a pathogenic germline variant in BRCA1 or BRCA2 have inherited it
from a parent.
• The parent with the variant may or may not have had a cancer diagnosis depending on the following
variables:
14 GeneReviews®
⚬ Penetrance of the variant

⚬ Gender of the parent
⚬ Age of the parent
⚬ Cancer risk reduction in the parent as a result of screening or prophylactic surgeries
⚬ Early death of the parent
• It is appropriate to offer molecular genetic testing to both parents of an individual with a BRCA1 or
BRCA2 germline pathogenic variant to determine which side of the family is at risk. Generally, the pattern
of cancers seen in the family usually guides which parent is tested first.
• Rarely, neither parent will be identified as having the BRCA1 or BRCA2 germline pathogenic variant. In
the years since the discovery of BRCA1 and BRCA2, de novo variants have been reported, but the rate
appears to be extremely low in these two genes (≤5%) based on the few studies performed to date [Hansen
et al 2008, Marshall et al 2009, Diez et al 2010, Garcia-Casado et al 2011, Kwong et al 2011, Zhang et al
2011, De Leeneer et al 2012].
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/
preimplantation genetic 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 Testing

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 testing for HBOC are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of
prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion
of these issues may be helpful.
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
16 GeneReviews®
Breast cancer resources

National Human Genome Research Institute (NHGRI)
research.nhgri.nih.gov/bic/resources.shtml
• Bright Pink
670 North Clark Street
Suite 2
Chicago IL 60654
www.brightpink.org
• 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: [email protected]
www.facingourrisk.org
• Gilda's Club Worldwide
48 Wall Street
11th Floor
New York NY 10005
Fax: 917-305-0549
www.cancersupportcommunity.org
• My46 Trait Profile
Hereditary Breast and Ovarian Cancer
• 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
www.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
www.stopbreastcancer.org
• National Cancer Institute (NCI)
6116 Executive Boulevard
Suite 300
Bethesda MD 20892-8322
Breast Cancer
Suite 300
Genetics of Breast and Ovarian Cancer (PDQ)
• 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
www.ovarian.org
• NCBI Genes and Disease
Breast and ovarian cancer
• Probability of Breast Cancer in American Women
National Cancer Institute Public Inquiries Office
Suite 300
18 GeneReviews®

Probability of Breast Cancer in American Women
• 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
www.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.
Phone: 877-465-6636 (Toll-free Helpline)
Fax: 972-855-1605
www.komen.org
• American Cancer Society (ACS)
250 Williams Street Northwest
Atlanta GA 30303
Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)
www.cancer.org
• CancerCare
275 Seventh Avenue
22nd Floor
New York NY 10001
Phone: 800-813-4673 (toll-free); 212-712-8400 (administrative)
Fax: 212-712-8495
www.cancercare.org
Suite 300
www.cancer.gov
• National Coalition for Cancer Survivorship (NCCS)
A consumer organization that advocates on behalf of all people with cancer
8455 Colesville Road
Suite 930
Silver Spring MD 20910
Phone: 877-622-7937 (toll-free); 301-650-9127
Fax: 301-565-9670
www.canceradvocacy.org
• Familial Ovarian Cancer Registry
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo NY 14263
Phone: 716-845-4503
www.ovariancancer.com
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 A. BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer: Genes and Databases
Gene Chromosome Locus Protein Locus-Specific Databases HGMD ClinVar
BRCA1 17q21.31 Breast cancer type 1 BRCA1 homepage - LOVD BRCA1 BRCA1
susceptibility protein Database of BRCA1 and BRCA2 sequence
variants that have been clinically reclassified
by a quantitative integrated evaluation
Breast Cancer Information Core (BRCA1)
BRCA1 @ ZAC-GGM
BRCA2 13q13.1 Breast cancer type 2 BRCA2 homepage - LOVD BRCA2 BRCA2
susceptibility protein Database of BRCA1 and BRCA2 sequence
variants that have been clinically reclassified
using a quantitative integrated evaluation
Breast Cancer Information Core (BRCA2)
Fanconi Anaemia Mutation Database
(FANCD1 - BRCA2)
BRCA2 @ ZAC-GGM
Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.
Table B. OMIM Entries for BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer (View All in OMIM)
113705 BREAST CANCER 1 GENE; BRCA1
114480 BREAST CANCER
20 GeneReviews®
Table B. continued from previous page.
600185 BRCA2 GENE; BRCA2

604370 BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 1; BROVCA1
612555 BREAST-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
Predicted Protein Change Reference Sequences
(Alias 1)
c.68_69delAG (185delAG or 187delAG) p.Glu23ValfsTer17
NM_007294.3
c.5096G>A p.Arg1699Gln
NP_009225.1
c.5266dupC (5385insC or 5382insC) p.Gln1756ProfsTer74
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of
variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society(varnomen.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].
22 GeneReviews®
Table 5. Selected BRCA2 Pathogenic Variants

DNA Nucleotide Change
Predicted Protein Change Reference Sequences
(Alias 1)
c.771_775delTCAAA (999del5) p.Asn257LysfsTer17
NM_000059.3
c.5946delT (6174delT) p.Ser1982ArgfsTer22
NP_000050.2
c.9976A>T p.Lys3326Ter
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of
variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.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
NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian.
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility.
Available online. 2010. Accessed 2-17-21.
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 2-217-21.
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset
conditions. Available online. 2017. Accessed 2-17-21.
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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)
36 GeneReviews®
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
License
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NLM Citation: Petrucelli N, Daly MB, Pal T.

BRCA1- and BRCA2-

BRCA1- and BRCA2-Associated Hereditary Breast and

Probability Models for BRCA1/2 Pathogenic Variants

Establishing the Diagnosis

Proportion of BRCA1/BRCA2- Proportion of Pathogenic Variants 2 Detected by Method

Table 2. continued from previous page.

Risk for Malignancy 1

Phenotype Correlations by Gene

Penetrance (Cancer Risk)

Genetically Related (Allelic) Disorders

Table 3. continued from previous page.

Cancer Susceptibility Syndrome / Lifetime Breast Cancer Risk & Other

Prevention of Primary Manifestations

Prevention of Secondary Complications

Evaluation of Relatives at Risk

Therapies Under Investigation

Risk to Family Members

⚬ Penetrance of the variant

Related Genetic Counseling Issues

Prenatal Testing and Preimplantation Genetic Testing

Breast cancer resources

Phone: 800-422-6237 (toll-free)

Table B. continued from previous page.

600185 BRCA2 GENE; BRCA2

Table 5. Selected BRCA2 Pathogenic Variants

Vichapat V, Garmo H, Holmqusit M, Liljegren G, Warnberg F, Llambe M, Fornander T, Adolfsson J,

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