BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer

Clinical Diagnosis

BRCA1 or BRCA2 hereditary breast/ovarian cancer is suspected in an individual who has one or more of the following:

• A personal history of early-onset (before age 50 years) breast cancer or early-onset breast and ovarian cancer at any age and/or bilateral (or multifocal) disease

• A family history of breast cancer or breast and ovarian cancer consistent with autosomal dominant inheritance

• A personal or family history of male breast cancer

Probability models have been developed to estimate the likelihood that an individual or family has a mutation in BRCA1 or BRCA2.

• Four older prior probability models [Couch et al 1997, Shattuck-Eidens et al 1997, Frank et al 1998] and BRCAPRO [Parmigiani et al 1998] are available. Each has unique attributes determined by the methods, sample size, and population used to create the model.
  
  Note: The BRCAPRO model is frequently updated; this is not reflected in the date of the citation.
  
  A new model, Tyrer-Cuzick [Tyrer et al 2004] accounts for family history, reproductive history, and personal history of benign breast disease and is being described as the most comprehensive breast cancer risk assessment model providing both empiric risks and mutation probabilities.

• Prevalence tables representing observations of deleterious mutations by Myriad Genetic Laboratories through its clinical testing service have been developed [Frank et al 2002]. These tables are frequently updated.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.

Genes. BRCA1 and BRCA2 are the genes associated with BRCA1 and BRCA2 hereditary breast/ovarian cancer.

Clinical uses

• Diagnostic testing

• Predisposition testing in at-risk relatives

• Genetic counseling

Clinical testing

• Targeted mutation analysis. Targeted mutation analysis may be population-specific and include mutations known to be found at greater frequencies in certain ethnicities (see Table 2).

• Comprehensive analysis. Sequence analysis combined with other methods can detect both common and family-specific BRCA1 and BRCA2 mutations, including five specific large genomic rearrangements of BRCA1. Sequence analysis or other mutation scanning methods are recommended when the mutation in a family is not known, except in individuals of Ashkenazi Jewish descent (see Probands of Ashkenazi Jewish ancestry).

Table 2. Molecular Genetic Testing used in BRCA1 and BRCA2 Hereditary Breast/Ovarian Cancer

Test Methods	Population	Mutations Detected	Mutation Detection Frequency 1	Test Availability
				BRCA1	BRCA2
Targeted mutation analysis	Ashkenazi Jewish heritage	BRCA1: 187delAG 2BRCA1: 5385insC 2BRCA2: 6174delT	90% 3	Clinical	Clinical
Comprehensive analysis 4	All affected individuals	BRCA1 and BRCA2 sequence variant and five specific large genomic BRCA1 rearrangements	>88% in families with demonstrated linkage to BRCA1 or BRCA2 5, 6

1. Proportion of affected individuals with a mutation(s) as classified by gene/locus, phenotype, population group, genetic mechanism, and/or test method

2. The BRCA1 mutations 187delAG and 5385insC are also known as "185delAG" and "5382insC," respectively.

3. Frank et al [1998]

4. As performed at Myriad Genetics, includes full sequence determination of both BRCA1 and BRCA2 and detection of the following five specific large genomic rearrangements of the BRCA1 gene: a 3.8-kb deletion of exon 13 and a 510-bp deletion of exon 22 described in individuals of Dutch ancestry [Petrij-Bosch et al 1997], a 6-kb duplication of exon 13 described in individuals of European (particularly British) ancestry [BRCA1 Exon 13 Duplication Screening Group 2000], a 7.1-kb deletion of exons 8 and 9 described in individuals of European ancestry [Rohlfs et al 2000] and a 26-kb deletion of exons 14-20 [Myriad Genetic Laboratories, unpublished]. The proportion of clinically significant alterations in BRCA1 and BRCA2 attributable to these genomic rearrangements is estimated at 10%-15% [Unger et al 2000].

5. In all affected individuals, the probability of finding a BRCA1 or BRCA2 cancer-predisposing mutation is dependent on the method used for DNA analysis and the a priori risk of the person tested of having a mutation in either gene based on the person's cancer history, family history, and ethnic background.

6. Other genomic rearrangements or some types of errors in RNA transcript processing will not be detected in the Myriad Genetic Laboratory protocol.

Interpretation of test results in a proband

• Targeted mutation analysis. Possible results in a proband when testing for the three common Ashkenazi Jewish mutations:

  • Mutation is absent in a proband. 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 mutation. The recommendation to proceed with sequence analysis following the failure to detect one of the three common Ashkenazi Jewish mutations in this population is based on clinical judgment, the a priori risk of harboring a mutation, and the residual likelihood that a BRCA1 or BRCA2 mutation (other than the three common mutations) is present in that individual.

  • Mutation is present in a proband. The presence of a germline mutation (i.e., a positive result) confers increased risk for BRCA1- or BRCA2-associated cancers. It is recommended that follow-up testing of at-risk relatives include targeted mutation analysis for all three of the common Ashkenazi Jewish mutations regardless of which mutation is found in the proband, because the coexistence of more than one founder mutation has been reported in some Ashkenazi Jewish families [Ramus et al 2001].

• Sequence analysis. Possible results in a proband:

  • Mutation is absent in a proband. Failure to detect a 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. The possibility remains that the cancer in the family is either associated with a mutation not detectable by the method of genetic testing used, is caused by a change in a different cancer susceptibility gene, or is the result of non-hereditary factors. Consequently, the family should be cautioned that the failure to detect a mutation does not eliminate the possibility of a hereditary factor in the family. For other issues to consider in interpretation of sequence analysis results, click here.

  • Mutation is present in a proband. 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 in a proband. Sequence analysis may reveal a novel BRCA1 or BRCA2 variation of uncertain clinical significance in a proband. Generally, this is a change in a single DNA nucleotide (missense mutation) that may or may not disrupt protein function. To further evaluate this result, the laboratory may request blood samples from additional members of the family (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 polymorphism of no clinical significance.

Interpretation of test results in an at-risk relative

• Family-specific mutation. Possible results when testing at-risk relatives for a mutation known to be present in an affected member:

  • Mutation is absent in the at-risk relative. 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 in an at-risk relative. 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

Probands of Ashkenazi Jewish ancestry. In persons of Ashkenazi Jewish heritage, three founder mutations are observed: 187delAG (BRCA1), 5385insC (BRCA1), and 6174delT (BRCA2). As many as one in 40 Ashkenazim has one of these three founder mutations [Struewing et al 1997]. Consequently, testing a person of Ashkenazi Jewish heritage initially for these three founder mutations by targeted mutation analysis can be an effective way to assess if the individual has a BRCA1 or BRCA2 cancer-predisposing mutation rather than first performing sequence analysis as recommended for all other populations. If no mutation is identified by targeted mutation analysis, the recommendation may be to proceed with sequence analysis. This recommendation is often based on clinical judgment, the a priori mutation risk, and the residual likelihood that a BRCA1 or BRCA2 mutation is present in that individual.

Family not known to have a BRCA1 or BRCA2 mutation. Testing in families is most likely to be informative if the first person to undergo testing has already had breast cancer and/or ovarian cancer, especially if the breast cancer occurred at an earlier age than usual (i.e., before 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 mutation, and who is less likely to have developed sporadic breast or ovarian cancer. In many families, this approach is not feasible because the affected relative is deceased or is not willing or able to participate in molecular genetic testing. In these instances, testing 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 mutation being present in the family.

Family known to have a BRCA1 or BRCA2 mutation. Once a deleterious mutation has been identified within a family, adult relatives (including family members without a cancer history) may then be tested for the same family-specific mutation with great accuracy. In most cases, relatives at risk need only be tested for the family-specific mutation. Exceptions:

• Individuals of Ashkenazi Jewish heritage who should be tested for all three founder mutations because of the coexistence of more than one founder mutation in some Ashkenazi Jewish families

• Individuals in whom a BRCA1 or BRCA2 mutation may be present in both maternal and paternal lines. For example, if a mutation is identified on the maternal side of the family, and if hereditary breast cancer and/or ovarian cancer is also suspected on the paternal side, it is appropriate to recommend that the individual undergo sequence analysis of BRCA1 and BRCA2, which would (1) detect the familial mutation from the maternal side and also (2) address whether a mutation is tracking on the paternal side as well.

Genetically Related (Allelic) Disorders

Germline mutations in BRCA2 have been associated with the following:

• Familial pancreatic cancer [Naderi & Couch 2002, Hahn et al 2003]

• Fanconi anemia complementation group FANCD1 [Howlett et al 2002]

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/BRCA2 mutations in breast cancer occurring in individuals with no known family history of breast cancer suggest that breast cancer in individuals with BRCA1 or BRCA2 cancer-predisposing mutations has a specific pathogenetic basis, which could lead to differences in prognosis. Accurate estimates of breast cancer prognosis in individuals with BRCA1/BRCA2 cancer-predisposing mutations would require prospective longitudinal studies with large numbers of women. Such studies have yet to be reported.

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 because survival has improved over time). 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. 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, e.g., if tumors in individuals with cancer-predisposing mutations indeed presented at more advanced stages. However, this would first require firm evidence (currently lacking) that stage at diagnosis is indeed different in women with BRCA1 or BRCA2 cancer-predisposing mutations from that in women with sporadic tumors [Pharoah et al 1999].

Given these limitations, most studies on prognosis of breast cancer have not found a significant difference in survival between individuals with BRCA1 or BRCA2 cancer-predisposing mutations and controls [Gaffney et al 1998, Johannsson et al 1998, Verhoog et al 1998, Lee et al 1999, Verhoog et al 1999], but studies reporting both better prognosis [Porter et al 1994, Marcus et al 1996] and worse prognosis [Foulkes et al 1997, Ansquer et al 1998, Stoppa-Lyonnet et al 2000, Brekelmans et al 2006] exist.

In a retrospective cohort study of individuals of Ashkenazi heritage with breast cancer, those with a BRCA1 mutation experienced poorer disease-specific survival compared to controls who did not have a BRCA1 mutation, but only among women not receiving adjuvant chemotherapy [Robson et al 2004]. Several studies have reported higher rates of contralateral breast cancer [Robson et al 1999, Stoppa-Lyonnet et al 2000, Haffty et al 2002, Brekelmans et al 2006] and ipsilateral breast cancers [Robson et al 1999, Haffty et al 2002, Seynaeve et al 2004] in women treated conservatively. In one case-control study the increased rate of ipsilateral breast cancers was only seen in individuals with a BRCA1 or BRCA2 mutation who had not undergone prophylactic oophorectomy [Pierce et al 2006]. The increase in second primary cancers reported in these studies has not translated into significant differences in survival.

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

The first study in which women with BRCA1 cancer-predisposing mutations were identified by molecular genetic testing found improved survival in 43 women with BRCA1 cancer-predisposing mutations (median survival of 77 months compared to 29 months in controls) [Rubin et al 1996]. This study was criticized for selection bias, lead-time bias (increased surveillance leading to earlier diagnosis in familial cases) [Burk 1997, Whitmore 1997], and differences in treatment received by individuals with cancer-predisposing mutations compared to historical controls [Cannistra 1997]. Similar improved survival was noted in a study of 25 women with BRCA1 cancer-predisposing mutations with stage III ovarian cancer [Aida et al 1998], and in Ashkenazi Jewish women treated with platinum-based chemotherapy [Cass et al 2003].

A population-based study in Sweden (n=38) and a Canadian study (n=44) found no differences in survival between women with BRCA1 cancer-predisposing mutations and controls [Brunet et al 1997, Johannsson et al 1998]. A short-term improvement seen in a case-control study from the Netherlands did not persist after five years [Zweemer et al 2001]; a case-control study at the University of Iowa also failed to find a survival advantage for women with BRCA1 inactivation [Buller et al 2002]. A population-based study in the UK including 133 women with BRCA1 cancer-predisposing mutations and 26 women with BRCA2 cancer-predisposing mutations with ovarian cancer found no difference in survival between individuals with cancer-predisposing mutations and women with ovarian cancer in whom genetic testing was negative or unavailable. Survival was worse in familial cases (five-year survival of 20%) compared to non-familial cases (five-year survival of 30%), but this difference was not observed after controlling for tumor stage at diagnosis.

The relative prognosis for women with ovarian cancer who have a BRCA1 or BRCA2 cancer-predisposing mutation is therefore unclear, but data showing an in vitro increased sensitivity to platinum-based drugs in BRCA1 mutant cells provide a biologic rationale for improved survival in women treated with platinum-based therapies [Lafarge et al 2001, Quinn et al 2003].

Pathology

• Breast cancer pathology. To summarize, BRCA1-related tumors show an excess of medullary histopathology, are of higher histologic grade, and are more likely than sporadic tumors to be estrogen receptor-negative and progesterone receptor-negative. At the molecular level, a higher frequency of TP53 mutations and less HER2/c-erbB-2/neu overexpression are observed than in sporadic tumors. These features include both favorable and adverse 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].
  
  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 BRCA1 and BRCA2 cancer-predisposing mutations compared to controls. Over 90% of tumors in women with BRCA1 cancer-predisposing mutations are serous, compared to approximately 50% in women without a BRCA1 cancer-predisposing 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 are more frequently bilateral than mucinous cancers. Preliminary support for distinct molecular pathways of carcinogenesis comes from the finding of differential expression of genes in BRCA1, BRCA2 and 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 mutation position.

It has been suggested that families with mutations in the ovarian cancer cluster region (OCCR) of exon 11 of the BRCA2 gene have a higher ratio of ovarian to breast cancer than families with mutations elsewhere in the BRCA2 gene. Recently, 440 families with a BRCA2 mutation were investigated for the presence of cancer of the ovary, male breast, pancreas, prostate, colon, and stomach, and melanoma in first- and second-degree relatives of mutation-positive individuals. Families with ovarian cancer were more likely to harbor mutations in the OCCR than elsewhere in the gene. Differences in ethnic groups were documented as well. 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 contribute to the phenotypic variation observed in families with BRCA2 mutations [Lubinski et al 2004].

Penetrance (Cancer Risk)

The penetrance of BRCA1 or BRCA2 cancer-predisposing mutations — or likelihood of cancer when a cancer-predisposing mutation is present — is the most significant clinical aspect of BRCA1 and BRCA2 mutations. The penetrance is uncertain and probably variable. The strongest evidence for variable risk comes from studies of multiple families with the same cancer-predisposing mutation within defined ethnic populations (see Prevalence). The accumulated evidence indicates that some individuals with cancer-predisposing mutations 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 mutation may have multiple primary cancers before age 50 years, while others with the same cancer-predisposing mutation may not develop cancer until after age 70 years [Abeliovich et al 1997, Levy-Lahad et al 1997], or not at all.

The following is a summary of cancer risk in individuals identified with cancer-predisposing mutations in the BRCA1 and BRCA2 genes.

Breast cancer risk estimates derived from families ascertained for high penetrance

• BRCA1. The initial studies of the penetrance of cancer-predisposing mutations in BRCA1 involved BRCA1 mutation-positive families ascertained by the presence of multiple individuals (usually four or more) affected with breast cancer or ovarian cancer at any age. The cancer risks seen in these families are high and may overestimate the risk within all families with BRCA1 cancer-predisposing mutations. The estimates of the cumulative risk of breast cancer for women with a BRCA1 cancer-predisposing mutation from these high-risk families are summarized in Table 3 [Easton et al 1995].
  
  While not as common as in families with a BRCA2 mutation, male breast cancer has been reported in families with a BRCA1 mutation [Liede et al 2004].
  
  BRCA2. Women with BRCA2 cancer-predisposing mutations appear to have a breast cancer risk similar to that of women with BRCA1 cancer-predisposing mutations [Ford et al 1994, Easton et al 1997, Ford et al 1998]. Current risk estimates are based on observations from high-risk families participating in research studies. The average age at which cancer occurs in women with BRCA2 cancer-predisposing mutations may be later than for women with BRCA1 cancer-predisposing mutations [Krainer et al 1997, Ford et al 1998]. The estimates of the cumulative risk of breast cancer for women with a BRCA2 cancer-predisposing mutation from high-risk families are summarized in Table 3.
  
  Male breast cancer has been observed in families with BRCA2 cancer-predisposing mutations, including some families with multiple cases of male breast cancer and no cases of female breast cancer [Couch et al 1996, Thorlacius et al 1996, Thorlacius et al 1997]. Of 26 high-risk families with at least one case of male breast cancer, 77% showed linkage to the BRCA2 locus [Ford et al 1998]. However, among males with breast cancer who were not selected on the basis of family history, only 4%-14% tested positive for a germline BRCA2 mutation [Couch et al 1997, Friedman et al 1997].
  
  In a large cohort of males with breast cancer in Finland, founder mutations in BRCA2 were tenfold higher among those with a family history of breast/ovarian cancer than those with no family history (44% vs. 3.6%) [Syrjakoski et al 2004]. For males with a BRCA2 mutation, the risk of breast cancer by age 80 years has been estimated at 6.9% [Thompson & Easton 2001].

Ovarian cancer risk estimates derived from families ascertained for high penetrance

• BRCA1. Cumulative risk of ovarian cancer is high but appears to be variable, and is presumed to differ with the specific BRCA1 cancer-predisposing mutation [Neuhausen et al 1996]. One model based on data from high-risk families estimates an average risk of 30% by age 60 years and 63% by age 70 years for women with a BRCA1 cancer-predisposing mutation [Easton et al 1995]. A second genetic trait may be involved; risk of ovarian cancer was twofold higher in women with a BRCA1 cancer-predisposing mutation who also had one or two rare alleles of the HRAS1 VNTR locus [Phelan et al 1996]. Among a consecutive series of women with ovarian cancer, the mean age of cancer diagnosis was 50 years for those with the 185delAG mutation [Levy-Lahad et al 1997].

• BRCA2. Based on data from high-risk families, cumulative risk of ovarian cancer in women with BRCA2 cancer-predisposing mutations is estimated to be less than 27% by age 70 years [Ford et al 1998]. Ovarian cancer has been seen in up to 48% of families with BRCA2 cancer-predisposing mutations [Thorlacius et al 1995, Couch et al 1996, Tavtigian et al 1996]. Among a consecutive series of women with ovarian cancer, the mean age of cancer diagnosis was 68 years for those with the 6174delT mutation [Levy-Lahad et al 1997].

Other cancer risk estimates derived from families ascertained for high penetrance

• BRCA1. The risk of prostate cancer is estimated to be threefold higher in men who have a BRCA1 cancer-predisposing mutation than in the general population. The cumulative risk is 8% by age 70 years [Ford et al 1994]. Although some data suggest that the risk of colon cancer may be fourfold higher, with an estimated cumulative risk of 6% by age 70 years [Ford et al 1994], more recent data question the association of colon cancer with BRCA1/BRCA2 hereditary breast/ovarian cancer [Niell et al 2004].

• BRCA2. An increased risk of prostate cancer and pancreatic cancer may also occur in individuals with BRCA2 cancer-predisposing mutations [Berman et al 1996, Easton et al 1997, Gayther et al 1997, Naderi & Couch 2002, Hahn et al 2003]. Furthermore, cancers of the larynx, esophagus, colon, stomach, gallbladder, bile duct, and hematopoietic system, as well as melanomas, have been observed in families with BRCA2 cancer-predisposing mutations [Berman et al 1996, Easton et al 1997, Breast Cancer Linkage Consortium 1999].
  
  Several studies have addressed the risk of cancer in less selected families. A study of Ashkenazi Jewish families based on a volunteer survey found that individuals with the 185delAG mutation (BRCA1), the 5382insC mutation (BRCA1), or the 6174delT mutation (BRCA2) had a 56% risk of breast cancer, a 16% risk of ovarian cancer, and a 16% risk of prostate cancer (by age 70 years); the incidence of colon cancer was not elevated [Struewing et al 1997]. No significant differences were observed in the risk of breast cancer between women with BRCA1 cancer-predisposing mutations and women with BRCA2 cancer-predisposing mutations [Struewing et al 1997]. In the families of Ashkenazi Jewish women with breast cancer who were ascertained through clinical studies and who had the BRCA2 6174del mutation, the lifetime risk of breast cancer was calculated to be 36% [Fodor et al 1998].

A sample of 1008 Ashkenazi Jewish index cases of breast cancer, unselected for family history, underwent molecular analysis across entire families. The lifetime risks for breast and ovarian cancer among those with a BRCA1 mutation were 81% and 54%, respectively. Risks for those with a BRCA2 mutation were 85% for breast cancer and 23% for ovarian cancer. In this study, the rates appeared to increase over time. Breast cancer risk by age 50 years for those with a mutation who were born before 1940 was 24% compared to a risk of 67% for those born after 1940 [King et al 2003].

In a study of Icelandic women, those with the 999del5 mutation (BRCA2) had a 37% risk of breast cancer by age 70 years [Thorlacius et al 1998]. The cancer risks in these studies were derived indirectly by genotyping the proband and using the family history to estimate the penetrance of the cancer-predisposing mutation. Not all family members were genotyped and examined. In addition, a number of women with a BRCA1 cancer-predisposing mutation who have a minimal family history of breast cancer have now been reported [Langston et al 1996, Abeliovich et al 1997, Levy-Lahad et al 1997, Ozcelik et al 1997, Richards et al 1997].

Among multiple-case breast cancer families attending Australian family cancer clinics, the cumulative risk for breast cancer by age 70 years for those with a BRCA1 or BRCA2 mutation was 64% [Scott et al 2003]. A combined analysis of 22 studies involving 8,139 individuals unselected for family history, estimated the risk for breast cancer by age 70 years to be 65% in those with a BRCA1 mutation, and 45% in those with a BRCA2 mutation. Corresponding rates for ovarian cancer were 39% for those with a BRCA1 mutation and 11% for those with a BRCA2 mutation. Risks in those individuals with a mutation were higher in families with a case of breast cancer diagnosed before age 35 years. This analysis also identified evidence for a reduction in risk in women from earlier birth cohorts [Antoniou et al 2003].

Anticipation

Anticipation is not observed.

Prevalence

BRCA1 cancer-predisposing mutations. The prevalence of cancer-predisposing BRCA1 mutations in the general population is estimated at between 1:500 and 1:1000. A comprehensive discussion of BRCA1 and BRCA2 population genetics is available [Szabo & King 1997]. Data from a population-based case-control study of breast cancer found a prevalence of BRCA1 mutations of 2.4% among cases. Heterozygosity for a BRCA1 mutation was increased in families with early-onset breast cancer, a history of ovarian cancer and Ashkenazi Jewish ancestry [Malone et al 2006].

The following describes specific BRCA1 cancer-predisposing mutations in two ethnic groups:

• Ashkenazi Jews. The 185delAG mutation in BRCA1 occurs with a frequency of about 1% in individuals of Ashkenazi Jewish descent [Struewing et al 1995, Oddoux et al 1996, Roa et al 1996, Struewing et al 1997]. Another BRCA1 mutation, 5382insC, has an estimated prevalence of 0.1%-0.15% [Roa et al 1996]. Both were initially observed in high-risk families. The 185delAG (BRCA1) and 6174delT (BRCA2) mutations have subsequently been found in 20%-30% of Jewish women diagnosed with early breast cancer [Abeliovich et al 1997, FitzGerald et al 1997] and in 45%-60% of Jewish women diagnosed with ovarian cancer [Abeliovich et al 1997; Levy-Lahad, unpublished data]. The frequency of the 185delAG and 6174delT mutations is higher among individuals with a family history of breast or ovarian cancer [Modan et al 1996, Levy-Lahad et al 1997], but individuals with the mutation who have little or no family history of cancer have been identified [Langston et al 1996, Abeliovich et al 1997, Levy-Lahad et al 1997, Richards et al 1997].

• Dutch. Although most cancer-predisposing BRCA1 mutations described involve only a few base pairs, studies in the Dutch population have identified three large deletions within BRCA1. These deletions were detected using Southern blot analysis and accounted for 36% of mutations on a Dutch sample of high-risk 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, such as mutation scanning, protein truncation testing (PTT), and direct sequencing.

BRCA2 cancer-predisposing mutations. The prevalence of cancer-predisposing BRCA2 mutations in the general population is unknown. From the prevalence of cancer-prone families, BRCA1 and BRCA2 cancer-predisposing mutations have been estimated to occur in approximately one to two persons per thousand. Among breast cancer cases in a population-based case-control study, the prevalence of BRCA2 mutations was 2.3% [Malone et al 2006].

The following describes specific BRCA2 cancer-predisposing mutations in two ethnic groups:

• Icelanders. The BRCA2 cancer-predisposing mutation 999del5 occurs in 0.6% of the Icelandic population and in 7.7% of women and 40% of men with breast cancer from Iceland [Thorlacius et al 1996, Thorlacius et al 1997, Arason 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].

• Ashkenazi Jews. The BRCA2 mutation 6174delT occurs with a frequency of about 1% in individuals of Ashkenazi Jewish descent [Struewing et al 1995, Oddoux et al 1996, Roa et al 1996, Struewing et al 1997]. This mutation was initially observed in high-risk families.

Evaluations Following Initial Diagnosis

Unaffected women who are diagnosed with a deleterious mutation in BRCA1 or BRCA2 are counseled at the time of disclosure about their options for screening and primary prevention.

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.

Prevention of Primary Manifestations

Individuals with breast cancer. Several studies have documented an excess of both ipsilateral and contralateral breast cancers among women with BRCA1 or BRCA2 mutations who were treated conservatively for their primary breast cancer, leading some to consider bilateral prophylactic mastectomies to minimize the risk of 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 have been suggested to reduce cancer risk in individuals who have a BRCA1 or BRCA2 cancer-predisposing mutation. These include prophylactic mastectomy and/or oophorectomy and chemoprevention. Neither strategy has been assessed by randomized trials or case-control studies in high-risk women.

Prophylactic surgeries (mastectomy and oophorectomy) have 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 what the optimal timing for the procedure is and how individuals undergoing the procedure should be followed long-term.

A retrospective cohort study of all women receiving prophylactic mastectomy at the Mayo Clinic in the state of Minnesota 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 BRCA1 and BRCA2 mutations. 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]. Nonetheless, the experience is that few women from high-risk families choose this procedure [Stefanek et al 1995].

In a more recent study, the incidence of breast cancer in 483 individuals with a BRCA1/BRCA2 mutation was measured. 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 of breast cancer by approximately 90% in women who have a BRCA1/BRCA2 cancer-predisposing mutation [Rebbeck et al 2004].

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]. Histologic evaluation of the tissues removed for risk reduction has revealed a wide spectrum of both 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 oophorectomy the peritoneum remains at risk for primary peritoneal cancer, with rates of approximately 2% following surgery [Piver et al 1993, Casey et al 2005].

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].

Chemoprevention. 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 of 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 BRCA1 mutations are more likely to be estrogen receptor-negative (see Natural History), it is predicted that tamoxifen may provide more benefit in women with BRCA2 mutations and therefore, several studies have been conducted to determine the benefit of tamoxifen prophylaxis in women with BRCA1 or BRCA2 cancer-predisposing mutations.

A subset analysis of the randomized trial evaluated the effect of tamoxifen on the incidence of breast cancer among cancer-free women with inherited BRCA1 or BRCA2 mutations and showed that tamoxifen reduced the risk of breast cancer by 62% among healthy women with a BRCA2 mutation [King et al 2001]. In a case-control study of 538 women with a BRCA1/BRCA2 mutation, tamoxifen use was associated with a 50% reduction in the risk of developing contralateral breast cancer [Narod et al 2000]. In a recent historical cohort study of 491 women with hereditary breast cancer, a 41% reduction in the risk of contralateral breast cancer was observed after ten years [Metcalfe et al 2005a]. Although tamoxifen appears to be effective in preventing breast cancer in women with BRCA1 or BRCA2 mutations, 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 as compared to those who did not.

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

Surveillance

Several strategies have been suggested to reduce cancer risk in individuals who have a BRCA1 or BRCA2 cancer-predisposing mutation. One includes cancer screening. None of the cancer screening strategies has been assessed by randomized trials or case-control studies in high-risk women.

A task force convened by the Cancer Genetics Consortium (CGSC), an NIH-sponsored consortium of researchers assessing the ethical, legal, and social implications of genetic testing for cancer risk, has established recommendations for cancer screening of individuals with a BRCA1 or BRCA2 cancer-predisposing mutation [Burke et al 1997]. The CGSC statement emphasized that recommendations are based on presumed benefit and may change as new evidence becomes available; therefore, affected individuals should be informed as to the limits of current knowledge regarding outcomes of risk-reducing strategies, and individual preference should be taken into account in decisions about follow-up. Recommendations similar to those of the CGSC are in use in 16 European family cancer centers [Vasen et al 1998]. The CGSC recommendations for individuals with a BRCA1 or BRCA2 cancer-predisposing mutation are discussed below [Burke et al 1997]:

Breast cancer screening. The breast cancer screening recommendations are based on data from families with cancer-predisposing BRCA1 or BRCA2 mutations, which indicate that elevated breast cancer risk begins in the late 20s or early 30s [Burke et al 1997, National Cancer Institute Statement on Mammography Screening 2002].

• Monthly breast self-examination starting in early adulthood

• Annual or semiannual clinical breast examination beginning at age 25-35 years

• Annual mammography beginning at age 25-35 years

Screening should be individualized based on the earliest age of onset in the family.

Men with BRCA1 and BRCA2 cancer-predisposing mutations 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 annual mammograms 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. However, these methods are still recommended in the absence of more effective means of screening.

• Annual or semiannual pelvic examination beginning at age 25-35 years

• Annual or semiannual transvaginal ultrasound examination with color Doppler beginning at age 25-35 years

• Annual serum CA-125 concentration beginning at age 25-35 years

Screening should be individualized based on the earliest age of onset in family.

A recent study evaluated ovarian cancer screening by means of pelvic examination, serum CA-125, and transvaginal ultrasound (TVU) monitoring in a series of high-risk women. By combining CA-125 and TVU results, a positive predictive value of 40% was achieved. However, three of the four early-stage tumors had normal screening tests prior to diagnosis, indicating that the diagnostic tools appear to be sensitive in detecting advanced-stage ovarian cancer only [Olivier et al 2006].

An emerging technology, the use of proteomic patterns in serum to identify early ovarian cancer [Petricoin et al 2002], may provide advances in ovarian cancer screening.

Prostate cancer screening. Men with cancer-predisposing BRCA1 and BRCA2 mutations appear to have an increased risk of 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 BRCA1/BRCA2 mutations, prostate cancer surveillance is consistently recommended at age 40 years and older.

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

Melanoma. Since both cutaneous and ocular melanomas are part of the BRCA2 phenotype:

• Annual clinical examinations of the skin are recommended for individuals with a BRCA2 mutation.

• Eye examinations by a specialist are also recommended for individuals with a BRCA2 mutation [Liede et al 2004].

Testing of Relatives at Risk

Once a BRCA1 or BRCA2 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]; they are 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). The CGSC task force concluded that data were insufficient to make recommendations concerning HRT for women with BRCA1 or BRCA2 mutations [Burke et al 1997].

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].

Rouleau et al [2004] demonstrated that women at high risk for breast cancer and ovarian cancer tend to avoid HRT when BRCA1/BRCA2 mutations are either suspected or confirmed.

Rebbeck et al [2005] evaluated breast cancer risk associated with HRT after bilateral prophylactic oophorectomy in a cohort of 462 women with BRCA1/BRCA2 mutations 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 of subsequent breast cancer in women with a BRCA1 or BRCA2 mutation.

Oral contraceptive use. One case-control study found a decreased risk of ovarian cancer in women with BRCA1 or BRCA2 cancer-predisposing mutations who took oral contraceptives for more than three years [Narod et al 1995]. These data are consistent with data from general population studies, which indicate a reduced risk of ovarian cancer with oral contraceptive use. The case-control study did not assess other outcomes such as the effect of oral contraceptives on breast cancer risk.

More recent studies have found reduced ovarian cancer risk associated with use of oral contraceptives and evidence for increasing risk reduction with increasing duration of use. Whittemore et al [2004] studied oral contraceptive use in 451 women with mutations 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 2004]. Furthermore, there is no evidence that use of current (after 1975) oral contraceptive formulations increases risk of early-onset breast cancer for women with BRCA1/BRCA2 mutations; therefore, it has been suggested that oral contraceptives should not be contraindicated for a woman with a BRCA1 or BRCA2 mutation [Milne et al 2005].

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

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Cancer-predisposing mutations in the BRCA1 and BRCA2 genes are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Virtually all individuals with a cancer-predisposing mutation in BRCA1 or BRCA2 have inherited it from a parent.

• The parent may or may not have had a cancer diagnosis depending upon the penetrance of the mutation, the gender of the parent with the mutation, the age of the parent with the mutation, and other variables.

• It is appropriate to offer molecular genetic testing to both parents of an individual with a BRCA1 or BRCA2 cancer-predisposing mutation.

• Occasionally, neither parent will be identified as having the BRCA1 or BRCA2 cancer-predisposing mutation. The number of individuals with a BRCA1 or BRCA2 cancer-predisposing mutation that has occurred as a de novo event is not known but is believed to be small.

Sibs of a proband

• The risk to the sibs of the proband depends upon the genetic status of the proband's parents.

• The risk that a sib of an index case will inherit the cancer-predisposing BRCA1 or BRCA2 mutation is 50% if one parent has the BRCA1 or BRCA2 cancer-predisposing mutation.

• The risk of developing cancer, however, depends upon numerous variables including the penetrance of the mutation, the gender of the individual, and the age of the individual.

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

Other family members of a proband. The risk to other family members depends upon the status of the proband's parents. If a parent is found to have a BRCA1 or BRCA2 mutation, his or her family members are at risk. The risk depends upon their position in the pedigree.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing 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 undisclosed adoption could also be explored.

Family planning. The optimal time for determination of genetic risk is before pregnancy.

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:

• Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of Genetic Counselors

• 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 cancer-predisposing BRCA1 or BRCA2 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 and prophylactic surgery.

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

• DNA banking. See for a list of laboratories offering this service.

• 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:

  • Cancer risk

  • Cancer screening protocols

  • Risk status for 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 and state laws protect against health insurance discrimination.)

  • Individual's emotional status (e.g., depression, anxiety, guilt)

  • Relationships with partner, children, extended family, friends

At-risk relatives who have not inherited the cancer-predisposing mutation identified in the proband are presumed to be at or above the general population risk of developing cancer, depending upon personal risk factors. Appropriate cancer screening such as that recommended by the American Cancer Society or the National Cancer Centers Network (NCCN) for individuals of average risk is recommended. Note: This presumption cannot apply to individuals who test negative for a BRCA1 or BRCA2 cancer-predisposing mutation if the proband in the family either has not undergone molecular genetic testing of BRCA1 or BRCA2 or did not have an identified BRCA1 or BRCA2 cancer-predisposing mutation.

Testing of at-risk asymptomatic relatives during childhood. Legitimate concerns regarding testing of at-risk individuals younger than age 18 years for adult-onset conditions (including BRCA1 or BRCA2 cancer-predisposing mutations) exist, including issues of informed consent among minors, the lack of proven surveillance or prevention strategies, and concerns about stigmatization and discrimination. Such testing is typically unavailable. See also the National Society of Genetic Counselors resolution on genetic testing of children and the 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 (Genetic Testing; pdf)

DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing for BRCA1 or BRCA2 mutations is technically possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

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 conditions such as BRCA1 and BRCA2 hereditary breast/ovarian cancer that do not affect intellect and have some treatment available are not common. 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, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

BRCA1

Normal allelic variants. 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].

Pathologic allelic variants. More than 800 deleterious mutations have been identified in BRCA1. While a small number of these mutations have been found 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 yet available. Nearly 50% of mutations identified in BRCA1 and BRCA2 sequencing studies are of uncertain clinical significance [Shattuck-Eidens et al 1997]. As research proceeds, some of these mutations will likely prove to be normal variants without clinical significance, while others may be pathologic and associated with an increased cancer risk. (For more information, see Table A: locus-specific databases and HGMD.)

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, that was identified based on this interaction [Wu et al 1996].

The BRCA1/BARD1 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 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, homozygous knockout mice have been developed. In most cases, the complete loss of function of 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, helping 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 missing or non-functional protein. In all cancers that have been studied from individuals with a disease-causing mutation, the wild-type allele is deleted, strongly suggesting that BRCA1 is in the class of tumor suppressor genes, i.e., genes 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 that BRCA1 is a tumor suppressor gene is that overexpression of the breast cancer type 1 susceptibility protein leads to growth suppression similar to that seen with the paradigmatic tumor suppressors TP53 and the retinoblastoma gene [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

Normal allelic variants. The BRCA2 gene encodes a 10.4-kb transcript composed of 27 exons.

Pathologic allelic variants. As with BRCA1, more than 800 deleterious BRCA2 mutations have been identified. (For more information, see Table A: locus-specific databases and HGMD.)

Mutations of unknown clinical significance: About one-third of mutations identified in BRCA1 and BRCA2 sequencing studies are of uncertain clinical significance (see NHGRI-BIC Database). As research proceeds, some of these mutations will likely prove to be normal variants without clinical significance, while others may be associated with an increased cancer risk.

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 susceptiblity protein (BRCA2) to RAD51. BRCA2 is normally located in the nucleus and contains phosphorylated residues [Bertwistle et al 1997]. The breast cancer type 2 susceptibility 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, homozygous knockout mice have been created. In most cases, the complete loss of function of 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 leading to 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].

Literature Cited

Published Statements and Policies Regarding Genetic Testing

Suggested Reading

Author History

Julie O Bars Culver, MS (1998-present)
Wylie Burke, MD, PhD; University of Washington, Seattle (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, New York (1998-2005)
Ephrat Levy-Lahad, MD; Sharre Zedek Medical Center, Jerusalem (1998-2007)
Nancie Petrucelli, MS (2002-present)

Revision History

• 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