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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer

Synonym: HBOC

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

Author Information
, MS
Wayne State University School of Medicine/Detroit Medical Center
Karmanos Cancer Institute, Cancer Genetic Counseling Service
Detroit, Michigan
, MD, PhD
Chair, Department of Clinical Genetics
Fox Chase Cancer Center
Philadelphia, Pennsylvania
, MD, PhD, FACMG
Professor, Molecular Medicine and Genetics, Pediatrics and Pathology
Wayne State University School of Medicine
Director, Clinical Genetics Services
Director, Molecular Genetics Diagnostic Laboratory, Detroit Medical Center University Laboratories
Detroit, Michigan

Initial Posting: ; Last Update: September 26, 2013.

Summary

Disease characteristics. Hereditary breast and ovarian cancer syndrome (HBOC), caused by a germline mutation in BRCA1 or BRCA2, is characterized by an increased risk for breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer. The lifetime risk for these cancers in individuals with a mutation in BRCA1 or BRCA2:

  • 40%-80% for breast cancer
  • 11%-40% for ovarian cancer
  • 1%-10% for male breast cancer
  • Up to 39% for prostate cancer
  • 1%-7% for pancreatic cancer

Individuals with BRCA2 mutations may also be at an increased risk for melanoma. Prognosis for BRCA1/2-related cancer depends on the stage at which the cancer is diagnosed; however, studies on survival have revealed conflicting results for individuals with germline BRCA1 or BRCA2 mutations when compared to controls.

Diagnosis/testing. An increased likelihood of a BRCA1 or BRCA2 mutation is suspected on the basis of certain personal and family history characteristics and various clinical criteria. A diagnosis of HBOC is made following molecular genetic testing in an individual or family with a germline BRCA1 or BRCA2 mutation. No currently available technique can guarantee the identification of all cancer-predisposing mutations in BRCA1 or BRCA2. Furthermore, mutations of uncertain clinical significance may be identified.

Management. Treatment of manifestations: Treatment of breast and ovarian cancer in individuals with BRCA1- or BRCA2-related tumors is similar to that for sporadic forms of these cancers; however, new classes of drugs that specifically target the BRCA1/2 signaling pathways are being studied.

Prevention of primary manifestations: Prophylactic mastectomy and/or oophorectomy and chemoprevention using tamoxifen (a partial estrogen antagonist) have been used, but have not been assessed by randomized trials or case-control studies in high-risk women.

Surveillance: Breast cancer screening in women and men relies on a combination of monthly breast self-examination, annual or semiannual clinical breast examination, annual mammography, and breast MRI. In 2007, the American Cancer Society (ACS) added annual breast MRI to their screening recommendations for individuals with a germline mutation in BRCA1 or BRCA2. 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. Prostate cancer screening relies on annual digital rectal examination and prostate-specific antigen (PSA) testing. Screening of asymptomatic individuals for pancreatic cancer is not generally recommended. In those with a germline mutation in BRCA2, annual clinical examinations of the skin and eye are recommended.

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

Genetic counseling. Germline mutations in BRCA1 and BRCA2 are inherited in an autosomal dominant manner. The vast majority of individuals with a BRCA1 or BRCA2 mutation 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 mutation have a parent affected with cancer. Each offspring of an individual with a BRCA1 or BRCA2 germline mutation has a 50% chance of inheriting the mutation. Prenatal testing is possible for pregnancies at increased risk if the cancer-predisposing mutation in the family is known; however, requests for prenatal diagnosis of adult-onset diseases are uncommon and require careful genetic counseling.

Diagnosis

Clinical Diagnosis

A mutation in BRCA1 or BRCA2 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, which are based on various professional society guidelines [ASHG 1994, US Preventive Services Task Force 2005, American Society of Breast Surgeons 2006, Lancaster et al 2007, ACOG Committee on Practice Bulletins 2009]. See also NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian (registration required):

  • Breast cancer diagnosed at age 50 or younger
  • Ovarian cancer
  • Multiple primary breast cancers either in the same breast or opposite breast
  • Both breast and ovarian cancer
  • Male breast cancer
  • Triple-negative (estrogen receptor negative, progesterone receptor negative, and HER2/neu [human epidermal growth factor receptor 2] negative) breast cancer
  • Pancreatic cancer with breast or ovarian cancer in the same individual or on the same side of the family
  • 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 mutation in the family

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

BRCA1 and BRCA2 Mutation Probability Models

Many models have been developed to estimate the likelihood that an individual or family has a germline mutation in BRCA1 or BRCA2 [Parmigiani et al 1998, Frank et al 2002, Antoniou et al 2004, Evans et al 2004, Tyrer et al 2004]. Each mutation probability model has its unique attributes determined by the methods, sample size, and population used to create it. These models include those using logistic regression, genetic risk models using Bayesian analysis (BRCAPRO and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [BOADICEA]), and empiric data such as the Myriad prevalence tables.

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 numerical 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 mutation, even among experienced providers [Euhus et al 2002, de la Hoya et al 2003].

The validity of several of the models has been compared in different studies, and the data show that these models perform reasonably well in typical breast-ovarian cancer families seen in cancer genetics clinics [Antoniou et al 2008a]. Most models do not include other BRCA-related cancers (e.g., pancreatic cancer, prostate cancer). Interventions that decrease the likelihood that an individual will develop cancer (such as oophorectomy and mastectomy) may influence the ability to estimate BRCA1 and BRCA2 mutation probability [Katki 2007]. Furthermore, one study has shown that the models are sensitive to the amount of family history information available and do not perform as well with a limited family structure, defined as having fewer than two first- or second-degree female relatives surviving beyond the age of 45 years in either lineage [Weitzel et al 2007].

The performance of the models can vary in specific ethnic groups as well [Oros et al 2006, Vogel et al 2007, Kurian et al 2008, Kurian et al 2009] suggesting that further information is needed to determine which model performs best in each ethnic group. More recently, the addition of breast tumor markers including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) has been shown to improve the performance of BRCAPRO and BOADICEA [Tai et al 2008, Mavaddat et al 2010, Biswas et al 2012].

As more individuals have undergone molecular genetic testing of BRCA1 and BRCA2, risk assessment models have improved. Nevertheless, there is an art to risk assessment and thus, mutation probability models cannot replace clinical judgment. Also, it is important to note that there are factors that could limit the ability to provide an accurate risk assessment (i.e., small family size, few female relatives, and/or prophylactic surgeries).

Table 1. Characteristics of Common Models for Estimating the Likelihood of a BRCA1/BRCA2 Mutation

 Myriad Prevalence Tables 1 BRCAPRO 2BOADICEA 3Tyrer-Cuzick 4
Method Empiric data from Myriad Genetics based on family and personal history reported on requisition formsStatistical modelStatistical modelStatistical model
Features of the Model Proband may or may not have breast or ovarian cancerProband may or may not have breast or ovarian cancerProband may or may not have breast or ovarian cancerProband must be unaffected
Considers age of breast cancer diagnosis as <50 y or >50 yConsiders exact age at breast and ovarian cancer diagnosisConsiders exact age at breast and ovarian cancer diagnosisAlso includes reproductive factors and body mass index to estimate breast cancer risk
Considers breast cancer in ≥1 affected relatives only if diagnosed <50 yConsiders prior genetic testing in family (i.e., BRCA1/BRCA2 mutation-negative relatives)Includes all FDR and SDR with and without cancer
Considers ovarian cancer in ≥1 relative at any ageConsiders oophorectomy statusIncludes AJ ancestry
Includes AJ ancestryIncludes all FDR and SDR with and without cancer
Very easy to useIncludes AJ ancestry
LimitationsSimplified/limited consideration of family structureRequires computer software and time-consuming data entryRequires computer software and time-consuming data entryDesigned for individuals unaffected with breast cancer
Early age of breast cancer onsetIncorporates only FDR and SDR; may need to change proband to best capture risk and to account for disease in the paternal lineageIncorporates only FDR and SDR; may need to change proband to best capture risk
May overestimate risk in bilateral breast cancer 5
May perform better in persons of N. Eur. origin than minority populations 6

From National Cancer Institute Genetics of Breast and Ovarian Cancer (PDQ®)

BOADICEA = breast and ovarian analysis of disease incidence and carrier estimation algorithm

FDR = first-degree relatives

SDR = second-degree relatives

AJ = Ashkenazi Jewish

1. Frank et al [1998]

2. Parmigiani et al [1998], Katki [2007]

3. Parmigiani et al [1998], Antoniou et al [2004]

4. Tyrer et al [2004]

5. Ready et al [2009]

6. Huo et al [2009], Kurian et al [2009]

A subsequent update of the SCO statement in 2010 emphasized the importance of educating the health care sector about administering genetic testing and utilizing appropriate management strategies. They also urged that genetic tests with uncertain clinical utility be administered in the context of clinical trials, and gave strong support for increased funding in clinical genetics [Robson et al 2010 (full text)].

Molecular Genetic Testing

Genes. BRCA1 and BRCA2 are the two genes in which mutations are associated with hereditary breast and ovarian cancer (HBOC).

Table 2. Summary Molecular Genetic Testing Used in BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer (NBOC)

Gene 1 Proportion of HBOC Attributed to Mutations in This GeneTest MethodMutations Detected 2
BRCA1See Figure 1, Figure 2Targeted mutation analysis Ethnic specific 3
Sequence analysis / mutation scanning 4, 5Sequence variants 6
Deletion / duplication analysis 7(Multi)exonic deletion; complex alleles
BRCA2 Targeted mutation analysisEthnic-specific
Sequence analysis / mutation scanning 4, 5Sequence variants 6
Deletion /duplication analysis 7(Multi)exonic deletion; complex alleles

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Targeted mutation analysis may be population-specific and include mutations known to be found at greater frequencies in individuals of certain ethnic backgrounds (see Figure 1). In persons of Ashkenazi Jewish heritage, three founder germline mutations are observed: c.68_69delAG (BRCA1), c.5266dupC (BRCA1), and c.5946delT (BRCA2). As many as one in 40 Ashkenazim have one of these three founder mutations [Struewing et al 1997].

4. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection frequencies for mutation scanning may vary considerably among laboratories depending on the specific protocol used.

5. Recommended when the mutation in a family is not known, except in individuals of Ashkenazi Jewish descent (see Testing Strategy, To confirm/establish the diagnosis in a proband Ashkenazi Jewish ancestry). Both sequence analysis and deletion analysis may be required to detect complex BRCA1 or BRCA2 alleles that have deletion of an exon or deletion of several hundred/thousand nucleotides along with novel inserted sequences (see Table A).

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Interpretation of test results in a proband

  • Targeted mutation analysis. Possible results in a proband when testing for the three common Ashkenazi Jewish mutations:
    • Mutations are absent. Because this testing detects only the three founder mutations associated with Ashkenazi Jewish ancestry failure to detect a mutation (i.e., a “negative” result) does not exclude the possibility that the individual has another predisposing BRCA1 or BRCA2 germline mutation. See Testing Strategy for further information about second-tier testing in this situation.
    • Mutation is present. The presence of a germline mutation (i.e., a “positive” result) confers increased risk for BRCA1- or BRCA2-associated cancers.
    • Result is inconclusive. Given the testing methodology that is used, a novel BRCA1 or BRCA2 variant of uncertain clinical significance may be detected adjacent to one of the three common Ashkenazi Jewish mutations. Because targeted mutation analysis is focused on a small fraction of the gene, this is a rare occurrence. Generally, this is a change in a single nucleotide that may or may not disrupt protein function. To further evaluate such a result, the laboratory may request blood specimens from additional family members (usually affected individuals and/or parents of the individual tested) to determine if the variant cosegregates with the cancer in the family. Such studies could reveal that the variant is either a pathogenic mutation or a benign sequence variant of no clinical significance.
  • Sequence analysis. Possible results in a proband:
    • No mutation is detected. Failure to detect a germline mutation in a proband provides limited information and must be interpreted with caution since the underlying cause of the cancer in the family has not been established. Other possibilities remain: the cancer in the family is (a) associated with a BRCA1 or BRCA2 germline mutation not detectable by sequence analysis, (b) caused by a change in a different cancer susceptibility gene, or (c) the result of non-hereditary factors. Consequently, the family should be cautioned that failure to detect a BRCA1 or BRCA2 germline mutation does not eliminate the possibility of hereditary cancer susceptibility in the family.
    • Mutation is present. The presence of a germline BRCA1 or BRCA2 mutation in a proband confers an increased risk for BRCA1- or BRCA2- associated cancers.
    • Result is inconclusive. Sequence analysis may reveal a DNA variant of uncertain clinical significance (VUS) in either BRCA1 or BRCA2. Family studies may be initiated in an attempt to determine if the variant segregates with the cancer phenotype. Over time, the VUS rate has declined with recent data from several laboratories indicating a VUS rate for BRCA1 and BRCA2 of 2.9% [Eggington et al 2012] and 4.4% [Ambry Genetics]. However, the VUS rate is dependent on the laboratory's testing experience and as such is expected to change over time as more laboratories begin to offer BRCA1/2 testing.
  • Deletion/duplication analysis. Deletion/duplication analysis can give the following results:
    • Deletion/duplication is absent. Failure to detect a deletion/duplication (i.e., a negative result) must be interpreted with caution since the underlying cause of the cancer in the family has not been established.
    • Deletion/duplication is present. The presence of a germline deletion/duplication in BRCA1 or BRCA2 (i.e., a positive result) confers an increased risk for BRCA1- or BRCA2-associated cancers.
  • Multi-gene panels for hereditary breast/ovarian cancer. Massively parallel sequence analysis and other high throughput methods allow testing for BRCA1 and BRCA2 along with additional genes that are known or suspected to contribute to the development of these cancers. Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time; a panel may not include a specific gene of interest.

Interpretation of test results in an at-risk relative

  • Family-specific mutation. Possible results when testing at-risk relatives for a germline mutation known to be present in an affected family member:
    • Mutation is absent. Failure to detect the mutation (i.e., a “negative” result) means that the person has not inherited the family-specific mutation and has at least the general population risks for BRCA1- or BRCA2-associated cancers.
    • Mutation is present. Presence of the germline mutation (i.e., a “positive” result) means that the person has inherited the family-specific mutation and is at an increased risk for BRCA1- or BRCA2-associated cancers.

Testing Strategy

To confirm/establish the diagnosis in a proband of Ashkenazi Jewish ancestry

To confirm/establish the diagnosis in a proband of a family not known to have a BRCA1 or BRCA2 germline mutation

  • Testing family members for a germline mutation is most likely to be informative if the first person to undergo testing has already had a BRCA1/2-associated cancer, particularly breast cancer and/or ovarian cancer, especially if the breast cancer occurred at an earlier age than usual (i.e., age <50 years). Thus, whenever possible, molecular genetic testing should be performed on the individual in the family who is most likely to have a BRCA1 or BRCA2 germline mutation, and who is less likely to have developed sporadic breast or ovarian cancer.
  • If the affected relative is deceased or is not willing or able to participate in molecular genetic testing, testing for a germline mutation with sequence analysis and deletion/duplication analysis may be performed on individuals without a cancer history with the understanding that failure to detect a mutation does not eliminate the possibility of a BRCA1 or BRCA2 germline mutation being present in the family.

Predictive testing for at-risk asymptomatic adult family members in a family known to have a BRCA1 or BRCA2 germline mutation. Once a germline mutation has been identified within a family, adult relatives (including family members without a cancer history) may be tested for the same family-specific germline mutation with great accuracy. In most cases, relatives at risk need only be tested for the family-specific germline mutation. However, exceptions to this include any of the following:

  • Individuals of Ashkenazi Jewish heritage, who should be tested for all three founder germline mutations because of reports of the coexistence of more than one founder germline mutation in some Ashkenazi Jewish families
  • Individuals in whom a BRCA1 or BRCA2 germline mutation may be present in both maternal and paternal lines. For example, if a germline mutation is identified on the maternal side of the family, and if HBOC is also suspected on the paternal side, it is appropriate to recommend that the individual undergo sequence analysis and deletion/duplication analysis of BRCA1 and BRCA2, which would (1) detect the familial germline mutation from the maternal side if present and also (2) address whether a germline mutation is tracking on the paternal side as well.

Clinical Description

Natural History

Breast cancer prognosis. The distinct pathologic features of BRCA1-related tumors (and perhaps BRCA2-related tumors) coupled with the relative paucity of somatic BRCA1 and BRCA2 mutations in breast cancer occurring in individuals with no known family history of breast cancer suggest that breast cancer in individuals with a BRCA1 or BRCA2 cancer-predisposing germline mutation has a specific pathogenetic basis, which could lead to differences in prognosis.

Most available data, derived from retrospective or indirect data, are based on small numbers (<50 cases) and are probably confounded by different biases and by lack of appropriate controls (which should be matched not only for age and stage of cancer at diagnosis but also for calendar year of diagnosis, as survival has improved in recent years). For example, in most studies of breast cancer prognosis, molecular genetic testing was not performed in the control group and controls were not matched to cases for stage at diagnosis.

In a retrospective cohort study of individuals of Ashkenazi heritage with breast cancer, those with a BRCA1 germline mutation experienced poorer disease-specific survival compared to controls who did not have a BRCA1 germline mutation, but only among women not receiving adjuvant chemotherapy [Robson et al 2004]. A large population-based cohort study of 3,220 women found that when controlled for age, tumor stage and grade, nodal status, hormone receptors, and year of diagnosis, there were no differences in recurrence rates or mortality between individuals with a detectable BRCA1/2 mutation and those without a BRCA1/2 mutation [Goodwin et al 2012]. However, some investigators have suggested that matching for stage at the time of diagnosis may mask real biologic differences between BRCA1/BRCA2-related tumors and sporadic tumors, for example, if tumors in individuals with a cancer-predisposing germline mutation indeed were first detected at more advanced stages.

Several studies have reported higher rates of contralateral breast cancer [Malone et al 2010, Pierce et al 2010, van der Kolk et al 2010, Metcalfe et al 2011a, Vichapat et al 2012] in women treated conservatively. Predictors of contralateral breast cancer (CBC) include younger age at diagnosis and family history of early-onset breast cancer [Malone et al 2010, Metcalfe et al 2011a]. The risk for CBC was decreased among women who had undergone prophylactic oophorectomy [Metcalfe et al 2011a].

Ipsalateral breast cancer is also increased in women who choose conservative surgery, compared to those who choose mastectomy. The risk is lower among women who have been treated with chemotherapy, and those who have had prophylactic oophorectomy [Metcalfe et al 2011b]. No difference in overall survival is observed [Pierce et al 2010].

Ovarian cancer prognosis. Studies on ovarian cancer survival in women with a BRCA1/BRCA2 cancer-predisposing germline mutation have yielded conflicting results as well, at least in part because of the same methodologic issues encountered in studies on breast cancer prognosis. See Breast cancer prognosis.

A pooled analysis of 26 observational studies found a more favorable survival rate among individuals with a detectable BRCA1 or BRCA2 mutation compared to individuals without a BRCA1/2 mutation, (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 mutation [Alsop et al 2012]. Similarly, platinum-sensitive epithelial ovarian tumors were more likely to have BRCA1/2 mutations than platinum-resistant tumors [Dann et al 2012]. These data are consistent with data showing an in vitro increased sensitivity to platinum-based drugs in cells with a BRCA1 mutation [Lafarge et al 2001, Quinn et al 2003].

Fallopian tube carcinoma is now a well-established component tumor of the BRCA1-related and BRCA2-related cancer spectrum.

Primary peritoneal cancer. Heterozygotes for a BRCA1 mutation are also at risk for primary papillary serous carcinoma of the peritoneum, a malignancy that is indistinguishable from serous epithelial ovarian carcinoma. Primary papillary serous carcinoma of the peritoneum has also been associated with BRCA2 mutations; like ovarian cancer, this malignancy occurs less frequently in those with a BRCA2 mutation than in those with a BRCA1 mutation [Casey et al 2005].

Pathology

Breast cancer pathology. 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]. At the molecular level, a higher frequency of TP53 mutations is observed in BRCA1-related tumors than in sporadic tumors. These features include both favorable and unfavorable prognostic factors.

Emerging data suggest that BRCA1-related breast cancers are more likely than sporadic tumors to be derived from the basal epithelial layer of cells of the mammary gland, cells thought to represent the breast stem cells and to give rise to cancers with the same high-grade features seen in BRCA1-related cancers [Foulkes et al 2003, Foulkes et al 2004, Lacroix & Leclercq 2005, Lakhani et al 2005, Atchley et al 2008].

Information regarding BRCA2-related tumors is more limited, but they do not seem to have a characteristic histopathology and are at least as likely to be hormone receptor-positive as control tumors.

Ovarian cancer pathology. An excess of serous adenocarcinomas has been observed in women with a BRCA1 or BRCA2 cancer-predisposing germline mutation compared to controls. Over 90% of tumors in women with a BRCA1 cancer-predisposing germline mutation are serous, compared to approximately 50% in women without a BRCA1 cancer-predisposing germline mutation [Rubin et al 1996, Aida et al 1998, Berchuck et al 1998, Lu et al 1999]. Serous adenocarcinomas are generally of higher grade and exhibit prominent intraepithelial lymphocytes, marked nuclear atypia, and abundant mitoses [Fujiwara et al 2012].

Careful histopathologic analysis of the fallopian tubes removed at the time of prophylactic oophorectomy has identified the fimbria as a potential site for primary fallopian tube carcinoma and tubal intraepithelial carcinoma. Many of these tubal carcinomas also stain for p53 protein, which is over-accumulated in serous carcinoma [Crum et al 2007]. These findings suggest that in addition to primary tubal carcinoma, the fimbria may represent the origin of some peritoneal and ovarian serous carcinomas [Carlson et al 2008].

Preliminary support for distinct molecular pathways of carcinogenesis comes from the finding of differential expression of genes in BRCA1/BRCA2-related ovarian cancer when compared to sporadic ovarian cancer using DNA microarray technology [Jazaeri et al 2002]. This approach may ultimately lead to the identification of unique histopathologic subtypes.

Genotype-Phenotype Correlations

Cancer risks may differ by gene and also by location of a mutation within the gene.

Ovarian cancer risk is considerably higher in women with a BRCA1 germline mutation as compared to women with a germline BRCA2 mutation.

It has been suggested that families with a mutation in the ovarian cancer cluster region (OCCR) of exon 11 of BRCA2 have a higher ratio of ovarian to breast cancer than families with a mutation elsewhere in BRCA2.

First- and second-degree relatives in 440 families with a BRCA2 mutation-positive individual were investigated for the presence of cancer of the ovary, male breast, pancreas, prostate, colon, and stomach, as well as melanoma [Lubinski et al 2004]. Findings included the following:

  • Families with ovarian cancer were more likely to harbor mutations in the OCCR than elsewhere in the gene.
  • Families of Polish ancestry had a lower frequency of pancreatic cancer than families of other ethnic origins, suggesting that both position of mutation and ethnic background may contribute to the phenotypic variation observed in families with a BRCA2 germline mutation.

To date, these genotype-phenotype correlations as they relate to the OCCR of exon 11 in BRCA2 have been based on studies of small numbers of mutation-positive individuals and thus have not been sufficiently established to use clinically in risk assessment and management.

Penetrance (Cancer Risk)

The penetrance of BRCA1 and BRCA2 germline mutations remains an active area of research. Estimates of penetrance vary considerably depending on the context in which they were derived. The strongest evidence for variable risk comes from studies of multiple families with the same cancer-predisposing germline mutation within defined ethnic populations (see Prevalence). The accumulated evidence indicates that some individuals with a cancer-predisposing germline mutation survive to an elderly age without developing cancer. Among those who develop cancer, the age of onset, as well as type of cancer, varies. No clear explanation exists for the observation that some individuals with a cancer-predisposing germline mutation may have multiple primary cancers before age 50 years, while others with the same cancer-predisposing germline mutation may develop cancer only after age 70 years [Levy-Lahad et al 2001, Antoniou et al 2008b], or not at all.

"Multiple-breast case families" (i.e., families with at least four members with breast cancer onset at age less then 60 years), especially if ovarian cancer is also present, may be enriched for mutations and have been shown to have substantial risks for both breast and ovarian cancer. Easton et al [1995] provided a lifetime breast cancer risk in BRCA1 heterozygotes of greater than 80%, the highest reported estimate to date. However, these risks may overestimate the risk within all families and therefore, may not apply to families with less severe cancer histories or "incident cases" (i.e., individuals with breast cancer not selected on the basis of family history of breast cancer) as illustrated in studies of unselected individuals with breast cancer whose estimated breast cancer risks have been in the 40% to 60% range [Hopper et al 1999]. In addition to these wide-ranging risk estimates, penetrance has been shown to vary within families with the same BRCA1 or BRCA2 mutation, suggesting that no ‘exact’ risk estimate can be applied to all individuals with a specific mutation.

The following is a table and summary of cancer risks in individuals identified with mutations in BRCA1 or BRCA2. No associated benign tumors or physical abnormalities are presently known to be associated with BRCA1/2 mutations.

Table 3. BRCA1- and BRCA2-Associated Cancers

Cancer TypeGeneral Population RiskMutation Risk
BRCA1BRCA2
Breast12%50%-80%40%-70%
Second primary breast3.5% within 5 years
Up to 11%
27% within 5 yrs12% within 5 yrs
40%-50% at 20 yrs
Ovarian1%-2%24%-40%11%-18%
Male breast 0.1%1%-2%5%-10%
Prostate15% (N. European origin)
18% (African Americans)
<30%<39%
Pancreatic0.50%1%-3%2%-7%

Female Breast and Ovarian Cancer

Germline mutation in BRCA1. The risk for BRCA1-related breast and ovarian cancer appears to be confined to epithelial malignancies of both organs.

  • According to a combined analysis of 22 population-based studies [Antoniou et al 2003] in which individuals with a BRCA1 mutation were unselected for family history [Antoniou et al 2003], the average risk by age 70 years for breast cancer was 65% (95% CI = 44% to 78%) and for ovarian cancer was 39% (95% CI = 18%-54%) [Antoniou et al 2003].
  • Another population-based study estimated BRCA1-related breast and ovarian cancer risk to age 80 years at 90% and 24%, respectively [Risch et al 2006].
  • When corrected for ascertainment, a meta-analysis of ten studies of individuals with a BRCA1 mutation reported cumulative risks for breast cancer to age 70 years of 57% and ovarian cancer of 40% [Chen et al 2006].
  • In both the United States and Europe, several retrospective studies of various cohorts of women with hereditary breast cancer have been conducted to estimate the risk for contralateral breast cancer (CBC).

Germline mutation in BRCA2. The risk for BRCA2-related breast and ovarian cancer also appears to be confined to epithelial malignancies of both organs.

  • In the 22 population-based studies of Antoniou et al [2003], the BRCA2- related risk estimates to age 70 years for both breast and ovarian cancer were 45% (95% CI = 33% to 54%) and 11% (95% CI = 4% to 18%) respectively.
  • In another population-based study, BRCA2-related breast and ovarian cancer risk estimates to age 80 years were 41% and 8.4% respectively [Risch et al 2006], the lowest ovarian cancer penetrance estimate yet reported.
  • When corrected for ascertainment, the cumulative cancer risks to age 70 years for breast and ovarian cancer in individuals with a germline BRCA2 mutation were reported as 49% and 18% respectively [Chen & Parmigiani 2007].
  • The risk for ovarian cancer, although lower than that observed in heterozygotes for a BRCA1 mutation, is still greatly increased above the general population.
  • Ovarian cancer in BRCA2 heterozygotes is more likely to occur after age 50 years than ovarian cancer in BRCA1 heterozygotes [Risch et al 2001].
  • The contralateral breast cancer risk in BRCA2 heterozygotes is 12% within five years of the initial breast cancer diagnosis [Metcalfe et al 2004].

Fallopian Tube Carcinoma

The relative risk for fallopian tube carcinoma in individuals with a pathogenic mutation in BRCA1 has been reported to be as high as 120 [Medeiros et al 2006].

Primary Peritoneal Cancer

The cumulative risk of developing primary peritoneal cancer is 3.9%-4.3% at 20 years following oophorectomy [Casey et al 2005, Finch et al 2006].

Male Breast Cancer

Male breast cancer is more commonly associated with a BRCA2 mutation than a BRCA1 mutation.

Prostate cancer. Overall, male BRCA1/2 carriers have up to a 30%-39% lifetime risk for prostate cancer [Breast Cancer Linkage Consortium 1999, Risch et al 2001, Thompson & Easton 2002].

Germline mutation in BRCA1

  • The risk for prostate cancer in males heterozygous for a BRCA1 mutation is increased, with a relative risk of approximately 1.8 [Thompson & Easton 2002], although the risk may vary significantly depending on the location of the BRCA1 mutation [Cybulski et al 2008].
  • Such cancers do not typically demonstrate a younger than usual age at diagnosis [Giusti et al 2003].

Germline mutation in BRCA2

Pancreatic Cancer

The presence of pancreatic cancer in a family with breast cancer may be a statistically significant predictor of a BRCA2 mutation [Petersen & Hruban 2003], although BRCA1 heterozygotes have also been found to have an increased risk for pancreatic cancer. The lifetime risk for pancreatic cancer in individuals with BRCA2 mutations is estimated at 2%-7% [Breast Cancer Linkage Consortium 1999, Risch et al 2001, Thompson & Easton 2002].

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 mutation [Breast Cancer Linkage Consortium 1999, Hearle et al 2003, van Asperen et al 2005].

Other Cancers

A variety of other cancers have been implicated, albeit inconsistently, as part of the BRCA1/2-related cancer spectrum [Brose et al 2002].

Germline mutation in BRCA1

  • The Breast Cancer Linkage Consortium reported statistically significantly increased relative risks for cancers of the pancreas, uterine body and cervix (only in heterozygous women age <65 years), with relative risks of 2.3, 2.6, and 3.7 respectively [Thompson & Easton 2002].

Germline mutation in BRCA2

  • The Breast Cancer Linkage Consortium reported statistically increased relative risks for cancers of the gallbladder, bile duct, stomach, and melanoma with relative risks of 3.5, 5.0, 2.6, and 2.6 respectively, the latter three sites being inconsistently associated with BRCA2 [Van Asperen et al 2005].

Note: (1) Data suggesting a causative link between endometrial cancer and mutations in BRCA1/2 are inconsistent; such cases may be related to tamoxifen exposure [Beiner et al 2007]; and (2) initial reports of increased colorectal cancer risk have generally not been replicated.

Cancer Risks in Specific Populations

The risk for breast cancer by age 70 years in heterozygotes with the two Ashkenazi founder BRCA1 mutations 185delAG and 5382insC are 64% (95% CI = 34% to 80%) and 67% (95% CI = 36% to 83%) respectively [Antoniou et al 2005]. The corresponding values for ovarian cancer are 14% (95% CI = 2% to 24%) and 33% (95% CI = 8% to 50%) respectively.

In an effort to eliminate inflated penetrance estimates suspected from studies of cancer families, 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% to 93%) and among BRCA2 heterozygotes to be 38% (95% CI = 20% to 68%). Using a similar study design, Satagopan et al [2002] found the estimated penetrance of ovarian cancer at age 70 years among BRCA1 heterozygotes to be 37% (95% CI = 25% to 71%) and among BRCA2 heterozygotes to be 21% (95% CI = 13%-41%).

In the US population, Chen et al [2006] estimated cumulative breast cancer risk in heterozygotes for a BRCA1 mutation to age 70 years at 46% (95% CI = 0.39% to 0.54%) and for ovarian cancer at 39% (95% CI = 0.30% to 0.50%), based on 676 Ashkenazi families and 1272 families of other ethnicities.

The risk for breast cancer by age 70 years to those heterozygous for the Ashkenazi BRCA2 6174delT mutation is 43% (95% CI = 14% to 62%) and for ovarian cancer is 20% (95% CI = 2% to 35%) [Antoniou et al 2005].

The breast cancer penetrance of the Icelandic BRCA2 999del5 mutation c.771_775delTCAAA was 17% by age 50 years and 37% by age 70 years [Thorlacius et al 1996].

Anticipation

There is a growing number of reports of anticipation in hereditary breast cancer.

  • A retrospective study of 132 BRCA1/2-mutation positive families found a statistically significant decreased age of onset (7.9 years) from mother to daughter. Findings were similar for individuals with germline BRCA1 and germline BRCA2 mutations [Litton et al 2012].
  • Another study of 623 familial breast/ovarian cancer families found a consistent shift to earlier age at diagnosis from mother to daughter, ranging from 6.8 years for BRCA1-mutation positive individuals to 12.1 years for BRCA-mutation positive individuals. Earlier age of onset was associated with progressive telomere shortening [Martinez-Delgado et al 2011].

Prevalence

Hereditary breast and ovarian cancer (HBOC) resulting from mutations in BRCA1 and BRCA2 is the most common form of both hereditary breast and ovarian cancers and occurs in all ethnic and racial populations. The overall prevalence of BRCA1/2 mutations in the general population (excluding Ashkenazim) is estimated at one in 400 [Anglian Breast Cancer Study Group 2000, Whittemore et al 2004b] but varies depending on ethnicity.

Few studies, however, have directly compared mutation prevalence by ethnic background [Szabo & King 1997, Liede & Narod 2002, Olopade et al 2003, Haffty et al 2006, John et al 2007]. In the United States, much of the focus has been on individuals of Ashkenazi (Central/Eastern European) Jewish ancestry.

The following describes specific BRCA1 and BRCA2 germline mutations in Ashkenazi Jews, the Dutch, and Icelanders; however, founder BRCA1 and BRCA2 mutations have also been identified in several other populations [Ferla et al 2007].

Ashkenazi Jews. Ashkenazi Jews have a substantially elevated risk for hereditary breast and ovarian cancer secondary to a high frequency of BRCA1/2 mutations mainly attributable to three well-described founder mutations. The combined frequency of the following three mutations in the Ashkenazi Jewish population is 1:40 [Oddoux et al 1996, Struewing et al 1997, King et al 2003]. This increased frequency influences genetic testing recommendations for individuals of Ashkenazi Jewish heritage (see Testing Strategy).

BRCA1

BRCA2

The prevalence of BRCA1 mutations in Ashkenazi Jewish women younger than age 65 years at diagnosis is 8.3% [John et al 2007].

The BRCA1 founder mutation, 185delAG, has been found in 20% of Ashkenazi Jewish women diagnosed with breast cancer before age 42 years [Offit et al 1996].

The BRCA2 founder mutation, 6174delT, is present in 8% of women diagnosed with breast cancer before age 42 years and in 1.5% of unselected Ashkenazim [Berman et al 1996, Roa et al 1996].

Dutch. Although most BRCA1 mutations described involve only a few base pairs, studies in the Dutch population have identified three large deletions within BRCA1. These deletions, detected using Southern blot analysis, accounted for 36% of mutations in a sample of high-risk Dutch families [Petrij-Bosch et al 1997]. Large deletions of BRCA1 may occur in other populations but may not be identified by the more commonly used PCR-based mutation screening approaches (e.g., mutation scanning, protein truncation testing [PTT], direct sequencing).

Icelanders. The BRCA2 mutation 999del5 occurs in 0.6% of the Icelandic population and in 10.4% of women and 38% of men with breast cancer from Iceland [Thorlacius et al 1998]. The mutation was seen in 17% of women diagnosed with breast cancer by age 50 years and in 4% of women diagnosed at later ages. Among individuals with the 999del5 mutation, 17 of 44 (39%) had no first- or second-degree relatives with cancer, suggesting incomplete penetrance of the mutation [Thorlacius et al 1996].

Differential Diagnosis

Syndromic breast cancer. Individuals with the following cancer susceptibility syndromes and/or genes have an elevated breast cancer risk. In many instances, 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.

  • Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of the following classic tumors: soft tissue sarcoma, osteosarcoma, pre-menopausal breast cancer, brain tumors, adrenocortical carcinoma (ACC), and leukemias. In addition, a variety of other neoplasms may occur. LFS-related cancers often occur in childhood or young adulthood and survivors have an increased risk for multiple primary cancers. LFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline mutation in TP53 regardless of family cancer history. At least 70% of individuals diagnosed clinically have an identifiable germline mutation in TP53, the only gene identified to date in which mutations are definitively associated with LFS. Inheritance is autosomal dominant.
  • Cowden syndrome (CS) is one of the phenotypes included in the PTEN hamartoma tumor syndrome (PHTS). CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually present by the late 20s and have macrocephaly, trichilemmomas, and papillomatous papules. The lifetime risk of developing breast cancer is 25%-50%, with an average age of diagnosis between 38 and 46 years. The lifetime risk for thyroid cancer (usually follicular, rarely papillary, but never medullary thyroid cancer) is approximately 10%. The risk for endometrial cancer, although not well defined, may approach 5%-10%. The diagnosis of PHTS is only made when a PTEN mutation is identified. Inheritance is autosomal dominant.
  • Hereditary diffuse gastric cancer (HDGC) confers an autosomal dominant susceptibility for diffuse gastric cancer, a poorly differentiated adenocarcinoma that infiltrates into the stomach wall causing thickening of the wall (linitis plastica) without forming a distinct mass. Diffuse gastric cancer is also referred to as signet ring carcinoma or isolated cell type carcinoma. The average age of onset of hereditary diffuse gastric cancer is 38 years (range: age 14-69 years). Mutation of CDH1 accounts for an estimated 30%-50% of HDGC. The majority of the cancers in individuals with CDH1 mutations occur before age 40 years. The estimated cumulative risk for gastric cancer by age 80 years is 67% for men and 83% for women. Women also have a 39%-52% risk for lobular breast cancer.
  • CHEK2. The CHEK2 variant c.1100delC (NM_007194.3) appears to confer an approximately 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]. Some evidence suggests a stronger association among families with early-onset breast cancer than those with later-onset breast cancer. A large case-control study in Poland also identified increased risks for thyroid, prostate, colon, and kidney cancer among individuals with one of the three CHEK2 founder alleles: c.1100delC, c.319+1G>A(IVS2+1G>A), and p.Ile157Thr (NM_007194.3) [Cybulski et al 2004].
  • Ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, frequent infections, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Inheritance is autosomal recessive.

    The cancer risk to individuals heterozygous for ATM disease-causing mutations is approximately four times that of the general population, primarily because of an increased risk for breast cancer [Swift et al 1991, Easton 1994, Athma et al 1996, FitzGerald et al 1997, Stankovic et al 1998, Geoffroy-Perez et al 2001, Olsen et al 2001, Teraoka et al 2001, Chenevix-Trench et al 2002, Sommer et al 2002, Bernstein et al 2003, Bretsky et al 2003, Thorstenson et al 2003, Renwick et al 2006]. Risk for cancer probably depends on multiple factors including tumor type, age at cancer onset, and whether the heterozygote has a missense or a truncating mutation [Gatti et al 2001, Concannon 2002, Scott et al 2002, Spring et al 2002]. It is estimated that approximately 15% of women with ATM mutations will develop breast cancer [Ahmed & Rahman 2006].
  • Lynch syndrome/hereditary non-polyposis colorectal cancer syndrome (HNPCC). Breast cancer has also been reported in families with Lynch syndrome, but consistent associations have not been demonstrated [Gruber & Petersen 2002, Muller et al 2002]. More recently, Walsh et al [2010] determined that 35 of 107 persons with breast cancer from the Colorectal Cancer Family Registry (Colon CFR) had a mutation in one of the genes associated with Lynch syndrome. Eighteen of the 35 (51%) showed immunohistochemical absence of the mismatch repair (MMR) protein that corresponded to the mutation in MMR tracking in the family. They concluded that analysis of breast cancer tissue may be a valid option for the detection of MMR deficiency in families in which tumors typically associated with Lynch syndrome are not available. However, given their limited study design, Walsh et al [2010] were not able to comment on whether the risk for breast cancer is increased in heterozygotes for a mutation associated with Lynch syndrome. Ovarian cancer is also increased in Lynch syndrome, with lifetime risks ranging from 4% to 12%. Unlike ovarian cancer associated with germline mutations in BRCA1/2, those associated with Lynch syndrome are more likely to be endometrioid or clear cell [Ketabi et al 2011].
  • Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. Peutz-Jeghers-type hamartomatous polyps are most common in the small intestine (jejunum, ileum, and duodenum), but can also occur in the stomach and large bowel and in nasal passages. In a study by Lim et al [2004], 8% of women with PJS developed breast cancer by age 40 years and 32% by age 60 years. Mutations in STK11 (LKB1) are found in a significant proportion of individuals with or without a positive family history. Inheritance is autosomal dominant.
  • Bloom syndrome is characterized by severe pre- and postnatal growth deficiency, highly characteristic sparseness of subcutaneous fat tissue throughout infancy and early childhood, and short stature throughout postnatal life that in most affected individuals is accompanied by an erythematous and sun-sensitive skin lesion of the face. A variety of cancers, including breast, skin, aerodigestive (i.e., head, neck, and esophagus), and gastrointestinal have been described [Schneider 2002]. Mutations in BLM (RECQL3) are causative. Inheritance is autosomal recessive.
  • Werner syndrome is characterized by the appearance usually in the 20s of features associated with normal aging and by predisposition to cancers including breast cancer, sarcomas, melanoma, thyroid cancer, and hematologic malignancies [Schneider 2002]. Mutations in WRN (RECQL2) are causative. Inheritance is autosomal recessive.
  • Xeroderma pigmentosum (XP) is characterized by sun sensitivity, ocular involvement, and greatly increased risk for cutaneous neoplasms. About 25% of affected individuals have neurologic manifestations. Both benign and malignant skin conditions are common. Gliomas of the brain and spinal cord, tumors of the lung, uterus, breast, pancreas, stomach, kidney, and testicles, and leukemia have been reported in a few individuals with XP cells from individuals with XP with defective nucleotide excision repair (NER) are hypersensitive to killing by UV in comparison to normal cells; unscheduled DNA synthesis is abnormal in XP cells. XP is known to be associated with mutations in XPA, ERCC3 (XPB), XPC, ERCC2 (XPD), DDB2 (XPE), ERCC4 (XPF), ERCC5 (XPG), ERCC1, and POLH (XP-V). Inheritance is autosomal recessive.
  • PALB2, so-named because it is a "Partner And Localizer of BRCA2," interacts with the BRCA2 protein and is also involved in DNA repair. The cumulative breast cancer risk among females who have a germline mutation in PALB2 is estimated to be increased by twofold [Tischkowitz et al 2007]. Germline mutations in PALB2 have been identified in families with multiple cases of pancreatic cancer, but the exact risk for pancreatic cancer conferred by germline mutations in PALB2 has not yet been established. Male breast cancer has also been observed in PALB2 mutation-positive breast cancer families [Casadei et al 2011, Ding et al 2011].
  • RAD51C and the family of RAD51-related genes are thought to encode proteins that are involved in DNA damage repair. The RAD51 proteins interact with numerous other DNA repair proteins, including BRCA1 and BRCA2. One of five RAD51-related genes, RAD51C, has been reported to be linked to both Fanconi anemia-like disorders and familial breast and ovarian cancers. The literature, however, has produced contradictory findings. Nevertheless, there is substantial evidence for a weak association between germline mutations in RAD51C and breast cancer and ovarian cancer.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

Unaffected women who are diagnosed with a cancer-predisposing germline mutation 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

The treatment of both breast and ovarian cancer in individuals with BRCA1- or BRCA2-related tumors is similar to that in sporadic forms of these diseases. National Comprehensive Cancer Network (NCCN) guidelines do suggest that for primary surgical treatment of breast cancer, women with a BRCA1 or BRCA2 mutation could consider bilateral mastectomy because of their elevated rate of ipsalateral and contralateral breast cancer. See National Comprehensive Cancer Network guidelines for the treatment of breast cancer (registration required).

Prevention of Primary Manifestations

Individuals with breast cancer. Several studies have documented an excess of both ipsilateral and contralateral breast cancers among women with a BRCA1 or BRCA2 germline mutation who were treated conservatively for their primary breast cancer, leading some to consider bilateral prophylactic mastectomy to minimize the risk for second tumors [Sabel 2002].

If breast conservation with lumpectomy and radiation therapy is chosen, other strategies such as prophylactic oophorectomy and/or close surveillance may be considered [Pierce 2002].

Individuals at risk. Several strategies to reduce cancer risk in individuals with a BRCA1 or BRCA2 germline mutation have been suggested. These include prophylactic mastectomy and/or oophorectomy and chemoprevention. Neither strategy has been assessed by randomized trials in high-risk women. However, there have been a number of large both retrospective and prospective observational studies of prophylactic surgeries.

Prophylactic Surgery

Prophylactic surgery (mastectomy and oophorectomy) has been proposed as a means of reducing cancer risk in people with genetic susceptibility to breast and ovarian cancer. Numerous studies have provided compelling evidence to support the use of risk-reducing surgery in high-risk women, but several important questions remain, such as the optimal timing for the procedure and long-term follow up of those undergoing the procedure.

Prophylactic mastectomy

  • A retrospective cohort study of all women undergoing prophylactic mastectomy at the Mayo Clinic over a 30-year period estimated a 90% reduction in breast cancer risk from the procedure. One third of the women in the Mayo Clinic study were considered to have a strong family history of cancer and experienced a risk reduction similar to that of the whole [Hartmann et al 1999].
  • In a subsequent follow up of this cohort, 176 women were tested for a BRCA1 and BRCA2 germline mutation. Of the 26 with a germline BRCA1 or BRCA2 mutation, none had developed breast cancer after a median follow up of 13 years [Hartmann et al 2001].
  • In a more recent study, the incidence of breast cancer in 483 individuals with a BRCA1 or BRCA2 germline mutation was studied. Breast cancer was diagnosed in two (1.9%) of 105 women who underwent bilateral prophylactic mastectomy and in 184 (48.7%) of 378 matched controls who did not have surgery, suggesting that bilateral prophylactic mastectomy reduces the risk for breast cancer by approximately 90% in women who have a BRCA or BRCA2 germline mutation [Rebbeck et al 2004].
  • Because of the increased risk for contralateral breast cancer after a primary breast cancer in women with germline BRCA1/2 mutations, there is a growing trend for these women to choose bilateral mastectomy rather than conservative surgery at the time of diagnosis [Tuttle et al 2007].

Prophylactic oophorectomy. 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].

  • A meta-analysis of ten case-control, retrospective, or prospective cohort studies found a statistically significant reduction in BRCA1/2-related ovarian or fallopian tube cancers (HR = 0.21, CI 0.19-0.39) [Rebbeck et al 2009].
    • Histologic evaluation of the tissues removed for risk reduction has revealed a wide spectrum of dysplastic and hyperplastic lesions as well as occult ovarian cancers and primary fallopian tube tumors, supporting the removal of both ovaries and fallopian tubes at the time of surgery [Leeper et al 2002, Olivier et al 2004, Powell et al 2005].
    • However, following risk-reducing salpingo-oophorectomy the peritoneum remains at risk for primary peritoneal cancer, with rates of approximately 2%-4% following surgery [Piver et al 1993, Casey et al 2005, Finch et al 2012].
  • Rebbeck et al [2004] also found a 53% risk reduction for breast cancer in women undergoing bilateral prophylactic oophorectomy. These observations were consistent with the findings of Olopade & Artioli [2004].
  • A multisite study of 1,079 women followed for a median of 30-35 months found that while there was a reduction in breast cancer risk for all heterozygotes undergoing prophylactic oophorectomy, the risk reduction was more pronounced in women heterozygous for a BRCA2 mutation than a BRCA1 mutation [Kauff et al 2008].

In addition to reducing the risk for breast/ovarian cancer, there is evidence that both prophylactic mastectomy and prophylactic oophorectomy confer an overall survival advantage [Domchek et al 2010]. Because of the growing consensus that the origin of most, if not all, serous ovarian tumors among women with a germline BRCA1/2 mutation is the distal segment of the fallopian tube, not the surface epithelium of the ovary, serious consideration is being given to performing bilateral salpingectomy as an interim measure to preserve ovarian function until the time of natural menopause [Medeiros et al 2006, Greene et al 2011]. Several important questions regarding prophylactic surgery remain, such as the optimal timing for these procedures and optimal long-term surveillance. The side effects of surgical menopause, including vasomotor symptoms, vaginal dryness, osteoporosis, and increased risk for heart disease must also be considered.

Tubal ligation. Several case-control studies have documented a reduction in risk for ovarian cancer after tubal ligation in the general population. A meta-analysis of 13 studies showed a reduction in risk for ovarian cancer of 34%, which persisted 10-14 years after the procedure [Cibula et al 2011]. There are no data on the benefits of tubal ligation among women with germline BRCA1/2 mutations.

Chemoprevention

Tamoxifen. A randomized clinical trial of treatment with tamoxifen (a partial estrogen antagonist) in women identified by the Gail model to have an increased breast cancer risk reported a 49% reduction in breast cancer in the treated group [Fisher et al 1998]. Gail et al [1999] concluded that tamoxifen prophylaxis was most beneficial in women with an elevated risk for breast cancer who were under age 50 years. However, tamoxifen reduced the incidence of breast cancers that were estrogen receptor positive, but not estrogen receptor negative. Since breast cancers occurring in women with a BRCA1 germline mutation are more likely to be estrogen receptor negative (see Natural History), it is predicted that tamoxifen may provide more benefit in women with a BRCA2 germline mutation and therefore, several studies have been conducted to determine the benefit of tamoxifen prophylaxis in women with a BRCA1 or BRCA2 germline mutation.

  • A subset analysis of the randomized trial evaluated the effect of tamoxifen on the incidence of breast cancer among cancer-free women with an inherited BRCA1 or BRCA2 mutation and showed that tamoxifen reduced the risk for breast cancer by 62% among healthy women with a BRCA2 germline mutation [King et al 2001].
  • In a case-control study of 538 women with a BRCA1 or BRCA2 germline mutation, tamoxifen use was associated with a 50% reduction in the risk of developing contralateral breast cancer [Narod et al 2000].
  • In a recent historic cohort study of 491 women with hereditary breast cancer, a 41% reduction in the risk for contralateral breast cancer was observed after ten years [Metcalfe et al 2005a].
  • Although tamoxifen appears to be effective in reducing the risk for breast cancer in women with a BRCA1 or BRCA2 germline mutation, tamoxifen use compared to other risk-reducing strategies is limited [Metcalfe et al 2005b].

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.

Oral contraceptive use has been associated with a reduction in ovarian cancer in several case-control studies in the general population. A meta-analysis of studies among women with a BRCA1/2 germline mutation found a significant reduction in ovarian cancer (RR = 0.50, CI 0.33-0.75), with increasing protection with longer duration of use [Iodice et al 2010].

  • Whittemore et al [2004a] studied oral contraceptive use in 451 women with a germline mutation of BRCA1 or BRCA2 and found a reduction in ovarian cancer risk of 14% among women who had ever used oral contraceptives ("ever-users") and 38% among long-term users, which is consistent with (though somewhat weaker than) the reduction observed in the general population [Whittemore et al 2004a].
  • There is no evidence that use of current (after 1975) oral contraceptive formulations increases risk for early-onset breast cancer for women with a BRCA1 or BRCA2 germline mutation; therefore, it has been suggested that oral contraceptives should not be contraindicated for a woman with a BRCA1 or BRCA2 germline mutation [Milne et al 2005].

Breast Feeding

A recent study found that women with a germline BRCA1 mutation who breast-fed for a cumulative total of more than one year had a statistically significant reduced risk for breast cancer [Jernstrom et al 2004].

Surveillance

Breast cancer screening recommendations for women with a hereditary breast cancer syndrome are based on the high risk for breast cancer and the potential for early age of onset.

Female breast cancer. Breast MRI has been studied as an adjunct to routine mammography in high-risk women.

  • Several prospective studies have examined the combination of mammography and breast MRI in women with hereditary breast cancer syndromes and/or strong family histories of breast cancer. In all of the studies, breast MRI out-performed mammography in sensitivity.
  • In addition, surveillance with breast MRI has shifted the stage at diagnosis from advanced stages to earlier and pre-invasive stages [Leach et al 2005, Kuhl et al 2010, Sardanelli et al 2011, Warner et al 2011].
  • As a result of this accumulating data, the American Cancer Society has recommended the addition of breast MRI to annual mammogram for women who have germline mutations in breast cancer susceptibility genes and/or those with a risk for breast cancer of 20%-25% or greater, as determined by an empiric risk model that is based on family history [Saslow et al 2007].
  • Similarly, the National Cancer Center Network has recently recommended the addition of breast MRI to standard mammography among women with a BRCA1 or BRCA2 germline mutation [Daly et al 2010].

Male breast cancer. Men with a BRCA1 or BRCA2 germline mutation are also at increased risk for breast cancer. Although no formal program of surveillance has been recommended, breast self-examination training and regular monthly practice are advised, in addition to semiannual clinical breast examination and the consideration of a baseline mammogram followed by an annual mammogram if gynecomastia or parenchymal/glandular breast density are detected on baseline study [Daly et al 2003].

Ovarian cancer screening. The ovarian cancer screening measures available (transvaginal ultrasound examination and serum CA-125 concentration) have limited sensitivity and specificity and have not been shown to reduce ovarian cancer mortality [Clarke-Pearson 2009, Buys et al 2011]. However, semiannual concurrent transvaginal ultrasound and serum CA-125 concentration starting 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.

Prostate cancer screening. Men with a BRCA1 or BRCA2 germline mutation appear to be at an increased risk for prostate cancer and therefore should be informed about options for prostate cancer screening [Burke et al 1997].

  • The American Cancer Society recommends annual digital rectal examination and prostate-specific antigen (PSA) testing beginning at age 50 years in the general population, with consideration of earlier screening for men in high-risk groups including those with a "strong familial predisposition" [Mettlin et al 1993].
  • Therefore, for men with a BRCA1 or BRCA2 germline mutation, prostate cancer surveillance is consistently recommended beginning at age 40 years

Pancreatic cancer screening. Pancreatic cancer is an established feature of the BRCA2 phenotype. The association of pancreatic cancer susceptibility and germline mutations in BRCA1, however, is less strong. Screening of asymptomatic individuals for pancreatic cancer is not generally recommended, but is possible in research settings.

Melanoma. Since both cutaneous and ocular melanomas are part of the BRCA2 phenotype, annual clinical examinations of the skin and eye examinations by a specialist may be appropriate.

Evaluation of Relatives at Risk

Once a cancer-predisposing BRCA1 or BRCA2 germline mutation has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial mutation 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

Therapies specifically targeted to the BRCA1 and/or BRCA2 pathways are under investigation [Farmer et al 2005]; discussion of them is beyond the scope of this GeneReview.

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].

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 mutation 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 negate the protective effect of bilateral prophylactic oophorectomy on the risk for subsequent breast cancer in women with a BRCA1 or BRCA2 germline mutation. In a matched case-control study of 472 postmenopausal women with a BRCA1 mutation, the use of HRT was associated with a reduction in breast cancer risk (OR = 0.58; 95% CI, 0.36-0.96) [Eisen et al 2008].

Smoking does not appear to be a risk factor for breast cancer among individuals with a BRCA1 or BRCA2 germline mutation [Ghadirian et al 2004].

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

Germline mutations in BRCA1 and BRCA2 are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband with a BRCA1/2 mutation

  • Virtually all individuals with a germline mutation in BRCA1 or BRCA2 have inherited it from a parent.
  • The parent with the mutation may or may not have had a cancer diagnosis depending on the following variables:
    • Penetrance of the mutation
    • 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 mutation to determine which side of the family is at risk.
  • Occasionally, neither parent will be identified as having the BRCA1 or BRCA2 germline mutation. In the years since the discovery of BRCA1 and BRCA2, approximately 5 de novo mutations (one in BRCA1 and four in BRCA2) have been reported in the literature, suggesting a low prevalence of de novo mutations in these two genes [Tesoriero et al 1999, van der Luijt et al 2001, Robson et al 2002, Zhang et al 2011].

Sibs of a proband with a BRCA1/2 mutation

  • 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 mutation is 50% if one parent has the BRCA1 or BRCA2 germline mutation.
  • The risk of developing cancer, however, depends on numerous variables including the penetrance of the mutation and the gender and age of the individual.

Offspring of a proband with a BRCA1/2 mutation

  • The offspring of an individual identified as having a BRCA1 or BRCA2 germline mutation have a 50% chance of inheriting the mutation.
  • The risk of developing cancer, however, depends on numerous variables including the penetrance of the mutation and the gender and age of the individual.

Other family members of a proband with a BRCA1/2 mutation. The risk to other family members depends on the status of the proband's parents. If a parent has a BRCA1 or BRCA2 germline mutation, 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 mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing germline mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction), or undisclosed adoption could also be explored. Although rare, de novo mutations in both BRCA1 and BRCA2 have been reported.

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 comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ®, National Cancer Institute)

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

For those who choose to learn more about molecular genetic testing, it is suggested that pre-test education include discussion of the following [American Society of Clinical Oncology 1997, Geller et al 1997, McKinnon et al 1997, American Society of Clinical Oncology 2003]:

  • The individual's motivation for requesting testing and preconceived beliefs about the test (Some at-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding such issues as reproduction, financial matters, and career planning; others may simply "need to know.")
  • The individual's perceptions of his/her risk of developing cancer
  • The individual's readiness for testing and optimal timing for testing
  • Alternatives to testing, such as DNA banking
  • Inability of genetic testing to detect the presence or absence of cancer
  • The individual's support systems and possible need for additional psychological support
  • The individual's need for privacy and autonomy
  • The possible effects of positive, negative, or uninformative test results on the following:
    • Risk status of other family members
    • Insurance coverage and employment (An individual found to have an inherited susceptibility to cancer could face discrimination in access to health insurance and/or employment, although federal laws including the passage of the Genetic Information Nondiscrimination Act and state laws protect against health insurance and employment discrimination.)
    • Individual's emotional status (e.g., depression, anxiety, guilt)
    • Relationships with partner, children, extended family, friends

At-risk adult relatives who have not inherited the cancer-predisposing germline mutation 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 mutation may still be at an elevated risk for breast cancer based on a breast biopsy history which 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 mutation 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 mutation.

Testing of at-risk asymptomatic relatives 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 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. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions.

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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the diasese-causing allele has been identified in the family, prenatal testing for a BRCA1 or BRCA2 germline mutation is technically possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for germline mutations in genes that predispose to adult-onset cancers which (like HBOC) do not affect intellect and have some treatment available are uncommon. 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.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which a BRCA1 or BRCA2 germline mutation has been identified.

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
  • National Alliance of Breast Cancer Organizations
    An advocacy group that serves as an umbrella for 370 breast cancer groups nationwide. Provides information, a newsletter, and treatment information. Also provides grants for programs on early detection and education.
    9 East 37th Street
    10th Floor
    New York NY 10016
    Phone: 888-806-2226; 212-889-0606
    Fax: 212-689-1213
    Email: nbcamquestions@yahoo.com
  • 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 Library of Medicine Genetics Home Reference
  • 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
  • Gilda Radner Familial Ovarian Cancer Registry
    Roswell Park Cancer Institute
    Elm and Carlton Streets
    Buffalo NY 14263-0001
    Phone: 800-682-7426 (toll-free)
    Email: gradner@roswellpark.org

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 Hereditary Breast/Ovarian Cancer: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for BRCA1 and BRCA2 Hereditary Breast/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 Symbol.

Pathogenic allelic variants. More than 1600 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. Although some research studies have suggested differences in cancer risk associated with different BRCA1 mutations, no definitive data on this point are available. 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. In the future, some of these may prove to be benign variants without clinical significance, while others may be pathogenic and associated with an increased cancer risk. (For more information, see Table A.)

Table 4. Selected BRCA1 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.68_69delAG
(185delAG or 187delAG)
p.Glu23ValfsTer17NM_007294​.3
NP_009225​.1
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 normally located in the nucleus and contains phosphorylated residues [Chen et al 1996]. It contains several recognizable protein motifs, including a RING finger domain near the N-terminus, two nuclear localization signals located on exon 11, an "SQ" cluster between amino acids 1280-1524, and 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]. RING fingers are cysteine-rich sequences that coordinate the binding of two zinc ions and are found in a number of diverse proteins. This type of domain may facilitate both protein-protein and protein-DNA interactions [Boddy et al 1994]. The RING finger in BRCA1 appears to specifically interact with another similar RING finger protein, BARD1, which was identified based on this interaction [Wu et al 1996].

The BRCA1/BARD1 protein complex enhances ubiquitin ligase activity, which is associated with the regulation of centrosome function [Sankaran et al 2006]. BARD1 and BRCA1 also share another conserved sequence known as the BRCT domain, a phylogenetically conserved sequence found in proteins involved in DNA repair and cell cycle regulation [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].

In order to study the function of BRCA1, orthologous knockout mice have been developed. In most cases, the complete loss of function of the mouse protein Brca1 results in embryonic lethality 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]. Finally, 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, that helps to maintain genomic integrity [Zhang et al 1998]. When this function is lost, it probably allows for the accumulation of other genetic defects that are themselves directly responsible for cancer formation. BRCA1 contains regions that are capable of inducing transcription [Chapman & Verma 1996, Monteiro et al 1996]. 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]. It is likely that these large proteins 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 BRCA1 mutations lead to frameshifts resulting in a missing or non-functional protein. In all cancers that have been studied from individuals with a BRCA1 germline mutation, the normal allele is deleted or inactivated, resulting in homozygous 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 paradigmatic 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 Symbol.

Pathogenic allelic 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], which 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.

Table 5. Selected BRCA2 Pathogenic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.5946delT
(6174delT)
p.Ser1982ArgfsTer22NM_000059​.3
NP_000050​.2
c.771_775delTCAAA
(999del5)
p.Asn257LysfsTer17

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 codes for 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 normally located in the nucleus and contains phosphorylated residues [Bertwistle et al 1997]. BRCA2 protein has no recognizable protein motifs and no apparent relation to the breast cancer type 1 susceptibility protein. Nonetheless, the proteins encoded by BRCA1 and BRCA2 appear to share a number of functional similarities that may suggest why mutations in these genes lead to a specific hereditary predisposition to breast and ovarian cancer. 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].

In order to study the function of BRCA2, orthologous knockout mice have been created. In most cases, the complete loss of function of murine Brca2 results in embryonic lethality 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, which serves to maintain genomic integrity [Zhang et al 1998]. When this function is lost, it probably allows for the accumulation of other genetic defects that are themselves directly responsible for cancer formation. Additional studies have attempted to attribute specific biochemical functions to BRCA2. The protein contains regions that are capable of inducing transcription [Milner et al 1997] and has histone acetyltransferase activity, potentially supporting its role in DNA repair and/or RNA transcription [Siddique 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 mutations reported to date consist of frameshift deletions, insertions, or nonsense mutations that predict premature truncation of protein transcription, consistent with the loss of function that is expected with clinically significant mutations in 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 College of Medical Genetics. Genetic susceptibility to breast and ovarian cancer: assessment, counseling and testing guidelines. Bethesda, MD: American College of Medical Genetics. Available online. 1999. Accessed 2-28-14.
  2. American College of Medical Genetics. Statement on population screening for BRCA-1 mutation in Ashkenazi Jewish women. Available online. 1996. Accessed 2-28-14.
  3. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2003. Accessed 2-28-14.
  4. American Society of Clinical Oncology. Recommended breast cancer surveillance guidelines. Available online. 1997. Accessed 2-28-14.
  5. American Society of Clinical Oncology. Update of recommended breast cancer surveillance guidelines. Available online. 1998. Accessed 2-28-14.
  6. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 2-28-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  7. Kaiser Permanente; An evidence-based BRCA1 testing guideline. Am J Hum Genet. 1997;59 Suppl:A293.
  8. National Cancer Institute. Statement on mammography screening. Available online. 2002. Accessed 2-28-14.
  9. National Comprehensive Cancer Network. Clinical practice guidelines in oncology, genetic/familial high-risk assessment: breast and ovarian. Available online (registration required). 2010.
  10. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 2-28-14.
  11. Pacific Northwest Regional Genetics Group. Points to consider: caution and counseling advised with BRCA1 and BRCA2 testing. Genet Northwest. 1997; XI:1, 3.
  12. Robson NE, Storm CD, Weitzel J, Wollins DS, Offit K. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. Available online. 2010. Accessed 2-28-14. [PubMed: 20065170]

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Suggested Reading

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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 (2002-present)
Judith L Hull, MS; Memorial Sloan-Kettering Cancer Center (1998-2005)
Ephrat Levy-Lahad, MD; Sharre Zedek Medical Center (1998-2007)
Nancie Petrucelli, MS (2002-present)

Revision History

  • 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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