Clinical Diagnosis

If one or more of the following features are present in a family, hereditary breast and ovarian cancer (HBOC) resulting from germline mutations in BRCA1 and BRCA2 is suspected and further risk evaluation is warranted [National Comprehensive Cancer Network 2010]:

• Early-age-onset (age <50 years) breast cancer including both invasive and ductal carcinoma in situ (DCIS) breast cancers.
• Two breast primaries or breast and ovarian/fallopian tube/primary peritoneal cancer in a single individual or two or more breast primaries or breast and ovarian/fallopian tube/primary peritoneal cancers in close (first- second- and third-degree) relatives(s) from the same side of the family.
• Populations at risk (e.g., Ashkenazi Jewish).
• Member of a family with a known BRCA1 or BRCA2 mutation.
• Any male breast cancer.
• Ovarian/fallopian tube/primary peritoneal cancer at any age.

Situations that may lower the threshold of suspicion for HBOC include the following:

• Families 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, as this may lead to an underrepresentation of female cancers despite the presence of a predisposing family mutation
• Oophorectomy at a young age in family members, which reduces the risk for both breast and ovarian cancer, as this could mask a hereditary susceptibility to both breast and ovarian cancer
• Presence of adoption in the lineage
• Populations at risk of having a BRCA1 or BRCA2 mutation (e.g., Ashkenazi Jewish descent)

Probability models have been developed to estimate the likelihood that an individual or family has a mutation in BRCA1 or BRCA2. Each model has its unique attributes determined by the methods, sample size, and population used to create it. Two such widely used models include BRCAPRO and Myriad II (see Table 1 for a comparison.

• BRCAPRO [Parmigiani et al 1998] is a computer-based Bayesian probability model that uses breast and/or ovarian cancer family history in first- and second-degree relatives to determine the probability that a BRCA1 or BRCA2 mutation accounts for the pattern of these cancers in the family. Key attributes include the population prevalence of mutations, age-specific penetrance, and Ashkenazi Jewish heritage. BRCAPRO is available as part of the CancerGene software. Note: The BRCAPRO model is frequently updated; this is not reflected in the date of the citation provided above.
• Myriad II is a set of prevalence tables categorized by ethnic ancestry (Ashkenazi Jewish or non-Ashkenazi Jewish), the age of onset (age <50 years or age >50 years) of breast cancer, and the presence of ovarian cancer in the patient and/or first- or second-degree relatives. Myriad II is based on actual test data from the Myriad Genetic Laboratories clinical testing service [Frank et al 2002]. Online prevalence tables are frequently updated.
• Other less commonly used probability models include the Manchester Scoring System, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA)™, and Tyrer-Cuzick [Antoniou et al 2004, Evans et al 2004, Tyrer et al 2004].

In 2003, the American Society of Clinical Oncology (ASCO) updated their policy statement on genetic testing for cancer susceptibility stating, “Given the known limitations and wide variations inherent in models for estimating mutation probability in a given family or individual, and the lack of such models for many cancer predisposition syndromes, it is neither feasible nor practical to set numerical thresholds for recommending genetic risk assessment services. The American Society of Clinical Oncology therefore recommends that evaluation by a health care professional experienced in cancer genetics should be relied on in making interpretations of pedigree information and determinations of the appropriateness of genetic testing, including determinations of appropriateness for reimbursement.” As such, when evaluating family histories for HBOC, a quantitative and qualitative assessment of the pedigree should be conducted before making testing recommendations. See .

Molecular Genetic Testing

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

Clinical testing

• 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).
• Sequence analysis combined with other methods can detect both common and family-specific BRCA1 and BRCA2 mutations. Sequence analysis or mutation scanning methods are recommended when the mutation in a family is not known, except in individuals of Ashkenazi Jewish descent (see Testing Strategy, Probands of Ashkenazi Jewish ancestry). Both sequence analysis and deletion analysis may be required to detect complex BRCA1 or BRCA2 alleles that have a deletion of an exon or a deletion of several hundred/thousand nucleotides along with novel inserted sequences (see Table A).
• Deletion/duplication analysis. Various methods can be used for the analysis of structural genomic abnormalities, such as large deletions, duplications, or rearrangements.

Figure

Figure 1. BRCA1 and BRCA2 Mutation Frequencies in Individuals of Ashkenazi Jewish Ancestry

1. Frank et al [2002]

2. Detected by targeted mutation analysis; see Tables 4 and 5

3. Detected by sequence analysis (more...)

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

View in own window

Gene Symbol	Proportion of Hereditary Breast/Ovarian Cancer Attributed to Mutations in This Gene	Test Method	Mutations Detected	Test Availability
BRCA1	See Figure 1, Figure 2	Targeted mutation analysis	Ethnic-specific	Clinical
		Sequence analysis	Sequence variants 1
		Deletion / duplication analysis 2	Exonic or multiexonic deletion; complex alleles
BRCA2		Targeted mutation analysis	Ethnic-specific	Clinical
		Sequence analysis	Sequence variants 1
		Deletion /duplication analysis 2	Exonic or multiexonic deletion; complex alleles

Test Availability refers to availability in the GeneTests™ Laboratory Directory. 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.

1. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions, missense, nonsense, and splice site mutations.

2. 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. See CMA.

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. Because this testing detects only the three founder mutations associated with Ashkenazi Jewish ancestry (i.e., c.68_69delAG [BRCA1], c.5266dupC [BRCA1], and c.5946delT [BRCA2]; see Figure 1, Figure 2, Table 4, Table 5), 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. The recommendation to proceed with sequence analysis and duplication/deletion 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 germline mutation, and the residual likelihood that a BRCA1 or BRCA2 germline mutation (other than the three common mutations) is present in that individual. However, to date, no large rearrangements have been identified in the high-risk Ashkenazi Jewish population [Spence et al 2007, Stadler et al 2010], thus the utility of deletion/duplication analysis in these individuals will likely be very limited.
  • Mutation is present. 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, particularly if both sides of the family are Ashkenazi Jewish, 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 germline mutation has been reported in some Ashkenazi Jewish families [Ramus et al 2001].
  • 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 pathologic mutation or a normal 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 the failure to detect a BRCA1 or BRCA2 germline mutation does not eliminate the possibility of hereditary cancer susceptibility in the family. For other issues to consider in the interpretation of sequence analysis results, click here.
  • 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 in either BRCA1 or BRCA2 . Family studies may be initiated in an attempt to determine if the variant segregates with the cancer phenotype. Between 10% and 15% of individuals undergoing genetic testing for BRCA1 and BRCA2 mutations are found to have a variant of uncertain clinical significance [Frank et al 2002].
• Deletion/duplication analysis. If no mutation or inconclusive results are reported after sequence analysis, testing for deletions or complex alleles in BRCA1 and/or BRCA2 may be considered. 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. Other remaining possibilities: the cancer in the family is (a) associated with a mutation not detectable by the method of deletion/duplication analysis used, (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 the failure to detect a deletion (or complex allele) does not eliminate the possibility of a hereditary susceptibility in the family.
  • 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.

Figure

Figure 2. Estimated Mutation Detection Frequences for BRCA1 and BRCA2

1. At least 30% a priori risk of having a mutation

2. 26% of > 20,000 samples

3. Examples of mutations detected by sequence (more...)

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

Probands of Ashkenazi Jewish ancestry

• Targeted mutation analysis. 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]. Consequently, testing a person of Ashkenazi Jewish heritage initially for these three founder mutations by targeted mutation analysis is an effective way to assess if the individual has a BRCA1 or BRCA2 germline mutation rather than first performing sequence analysis as recommended for all other populations.
• Sequence analysis. If no mutation is identified by targeted mutation analysis, it may be appropriate to proceed with sequence analysis. This decision is based on clinical judgment, the a priori mutation risk, and the residual likelihood that a BRCA1 or BRCA2 germline mutation is present in that individual.
• Deletion/duplication analysis. Since no exonic/multiexonic deletions have been detected in the high-risk Ashkenazi Jewish population tested to date [Spence et al 2007, Stadler et al 2010], further testing using deletion/duplication analysis may not be necessary in this population.

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 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 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 (followed by deletion/duplication analysis when appropriate) 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 followed by 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.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the BRCA1 or BRCA2 germline mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 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.

Accurate estimates of breast cancer prognosis in individuals with a BRCA1/BRCA2 cancer-predisposing germline mutation 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 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. 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. However, this would first require firm evidence (currently lacking) that stage at diagnosis is indeed different in women with a BRCA1 or BRCA2 cancer-predisposing germline mutation 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 a BRCA1 or BRCA2 cancer-predisposing germline mutation and controls [Gaffney et al 1998, Johannsson et al 1998, Verhoog et al 1998, Lee et al 1999, Verhoog et al 1999, Brekelmans et al 2007, Rennert et al 2007, Budroni et al 2009, Kriege et al 2009], but studies have reported both a better prognosis [Porter et al 1994, Marcus et al 1996] and a worse prognosis [Foulkes et al 1997, Ansquer et al 1998, Stoppa-Lyonnet et al 2000, Brekelmans et al 2006].

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]. 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 germline 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 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.

A population-based study in Sweden (n=38) and a Canadian study (n=44) found no differences in survival between women with a BRCA1 cancer-predisposing germline mutation 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 small case-control study from the United Kingdom found both higher complete response rates (81.8% vs 43.2%; P=.004) and overall survival (95.5% vs. 59.1%; P=.002) for BRCA mutation-positive patients [Tan et al 2008]. The National Israeli Study of Ovarian Cancer reported significantly better median survival (53.7 months vs. 37.5 months; P=.002) and five-year survival rates (38.1% vs 24.5%; P=<.001) for those who had an Ashkenazi founder mutation compared to those who did not [Chetrit et al 2008]. Two population-based studies report a greater survival benefit among those who were BRCA2 mutation positive than among those who were BRCA1 mutation positive [Pal et al 2007, Byrd et al 2008].

The relative prognosis for women with ovarian cancer who have a BRCA1 or BRCA2 cancer-predisposing germline 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. 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 are more frequently bilateral than mucinous cancers.

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.

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.

Penetrance (Cancer Risk)

The penetrance of BRCA1 and BRCA2 germline mutations is the most significant clinical aspect of HBOC with breast and ovarian cancer being the predominant phenotype. 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 2008], 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 breast cancer patients 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 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.

BRCA1 – Female Breast and Ovarian Cancer Risks

• 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].
• The contralateral breast cancer risk in heterozygotes for a BRCA1 mutation is 27% within five years of the initial breast cancer diagnosis [Metcalfe et al 2004].
• The risk for BRCA1-related breast and ovarian cancer appears to be confined to epithelial malignancies of both organs.

BRCA1 – Other Related Cancer Risks

• Fallopian tube carcinoma is now a well-established component tumor of the BRCA1-related cancer spectrum, with relative risks reported as high as 120 [Medeiros et al 2006].
• 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, with cumulative risks of 3.9%-4.3% at 20 years following oophorectomy [Casey et al 2005, Finch et al 2006].
• 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]. Furthermore, such cancers do not typically demonstrate a younger than usual age at diagnosis [Giusti et al 2003].
• A variety of other cancers have been implicated, albeit inconsistently, as part of the BRCA1-related cancer spectrum [Brose et al 2002].
  • The most convincing associations are an increased risk for pancreatic cancer [Lynch et al 2005] and male breast cancer [Fentiman et al 2006, Tai et al 2007] with the cumulative breast cancer risks to age 70 years of 1.2% among males heterozygous for a BRCA1 mutation.
  • The Breast Cancer Linkage Consortium also 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].
  • Data suggesting a causative link between endometrial cancer and mutation in BRCA1/2 are inconsistent; such cases may be related to tamoxifen exposure [Beiner et al 2007].
• Initial reports of increased colorectal cancer risk have generally not been replicated.

BRCA2 – Female Breast and Ovarian Cancer Risks

• 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 BRCA2 heterozygotes 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 (1.4%). 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].
• As for BRCA1, the risk for BRCA2-related breast and ovarian cancer appears to be confined to epithelial malignancies of both organs as well.

BRCA2 – Other Related Cancer Risks

• Fallopian tube carcinoma has also been associated with BRCA2 mutations [Aziz et al 2001], as has primary papillary serous carcinoma of the peritoneum; 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].
• Male breast cancer is more commonly associated with a BRCA2 mutation than a BRCA1 mutation.
• The cumulative probability of breast cancer to age 70 years in males with a BRCA2 mutation has been reported at 6% [Fentiman et al 2006] and 6.8% [Tai et al 2007].
• The relative risk for prostate cancer in males with a BRCA2 mutation is 4.6 [Breast Cancer Linkage Consortium 1999]; in contrast to BRCA1-related prostate cancer, it may demonstrate a younger-than-usual age at diagnosis [Tryggvadottir et al 2007].
• 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 Breast Cancer Linkage Consortium reported statistically increased relative risks for cancers of the pancreas, gallbladder and 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].
• As with BRCA1, 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 to 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 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

Anticipation is not observed.

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 is estimated to be from 1:400 to 1:800 [Ford et al 1994, Claus et al 1996, Whittemore et al 1997], but varies depending on ethnicity.

Few studies, however, have directly compared mutation prevalence by ethnic background [Szabo & King 1997, Leide & 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 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

• 187delAG (NC_000017.9). This mutation occurs with a frequency of about 1.1% in individuals of Ashkenazi Jewish descent [Struewing et al 1995, Oddoux et al 1996, Roa et al 1996, John et al 2007].
• 5385insC (g.38462606dupC). This mutation has an estimated prevalence of 0.1%-0.15% [Roa et al 1996].

BRCA2

• 6174delT occurs with a frequency of about 1.5% [Struewing et al 1995, Oddoux et al 1996, Roa et al 1996, Struewing et al 1997].

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 were detected using Southern blot analysis and 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, such as mutation scanning, protein truncation testing (PTT), and 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].

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.

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.

Prophylactic surgery (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 the optimal timing for the procedure and long-term follow-up of those undergoing the procedure.

A retrospective cohort study of all women undergoing 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 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].

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]. 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]. 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.

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 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.

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

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

Breast cancer screening. The National Comprehensive Cancer Network (NCCN) has published practice guidelines for the management of individuals with a hereditary breast/ovarian cancer risk [Daly et al 2010]. See (registration required).

Breast cancer screening guidelines include:

• Monthly breast self-examination starting in early adulthood
• Semiannual clinical breast examination beginning at age 25 years
• Annual mammography and breast MRI beginning at age 25-35 years

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

Recent studies have evaluated the efficacy of breast MRI screening in women with a BRCA1 or BRCA2 germline mutation [Kriege et al 2004, Warner et al 2004, Warner & Causer 2005]. One such study compared the sensitivity and specificity of four methods of breast cancer screening (mammography, ultrasound, MRI, and clinical breast examination [CBE]) in women with a BRCA1 or BRCA2 germline mutation (Table 3). In 236 Canadian women with a BRCA1 or BRCA2 germline mutation evaluated using these four methods, 22 cancers were detected. The authors concluded that MRI-based screening is likely to become the standard of breast cancer screening for women with a BRCA1 or BRCA2 germline mutation [Warner et al 2004]. 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].

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]. However, semiannual concurrent transvaginal ultrasound and CA125 starting at age 35 years may be considered for those women who have not elected to undergo prophylactic oophorectomy, starting at age 35 years, or individualized based on the earliest age of onset in the family.

Prostate cancer screening. Men with a BRCA1 and 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 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 and eye examinations by a specialist 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.

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].

Oral contraceptive use. One case-control study found a decreased risk for ovarian cancer in women with a BRCA1 or BRCA2 germline mutation 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 for 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 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 2004]. Furthermore, 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].

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].

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.

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 may or may not have had a cancer diagnosis depending on 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 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. The number of individuals with a BRCA1 or BRCA2 germline mutation that has occurred as a de novo event is not known but is believed to be small [Tesoriero et al 1999, Robson et al 2002, van der Luijt et al 2001].

Sibs of a proband with a BRCA1/2 mutation

• The risk to full siblings of the proband depends on the genetic status of the proband's parents.
• The risk that a sibling 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

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 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
• 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:
  • Cancer risk
  • Cancer screening protocols
  • 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 recent passage of the Genetic Information Non-Discrimination 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 during childhood. Legitimate concerns regarding testing of at-risk individuals younger than age 18 years for adult-onset conditions (including BRCA1 or BRCA2 germline mutations) exist, including issues of informed consent among minors, the lack of proven surveillance or prevention strategies at that age, and concerns about stigmatization and discrimination. Such testing is typically not recommended. (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.)

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

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 about 15 to 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 germline mutations that predispose to adult-onset cancers which, like BRCA1 and BRCA2 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 available for families in which a BRCA1 or BRCA2 germline mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Published Guidelines/Consensus Statements

1. American College of Medical Genetics. Genetic susceptibility to breast and ovarian cancer: Assessment, counseling and testing guidelines. Available online. 1999. Accessed 3-26-13.
2. American College of Medical Genetics. Statement on population screening for BRCA-1 mutation in Ashkenazi Jewish women. Available online. 1996. Accessed 3-26-13.
3. American Society of Clinical Oncology. Recommended breast cancer surveillance guidelines. Available online. 1997. Accessed 3-26-13.
4. American Society of Clinical Oncology. American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility (pdf). Available online. 2003. Accessed 3-26-13.
5. American Society of Clinical Oncology. Update of recommended breast cancer surveillance guidelines. Available online. 1998. Accessed 3-26-13.
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 3-26-13. [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 3-26-13.
9. National Society of Genetic Counselors. Statement on genetic testing for adult-onset disorders. Available online. 1997. Accessed 3-26-13.
10. National Comprehensive Cancer Network. Clinical practice guidelines in oncology, genetic/familial high-risk assessment: breast and ovarian. Available at: www​.nccn.org (registration required). 2010. Accessed 7-24-12.
11. Pacific Northwest Regional Genetics Group. Points to consider: caution and counseling advised with BRCA1 and BRCA2 testing. Genet Northwest. 1997; XI:1, 3.

Literature Cited

1. Abbott DW, Freeman ML, Holt JT. Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J Natl Cancer Inst. 1998;90:978–85. [PubMed: 9665145]
2. Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006;25(43):5906–5911. [PubMed: 16998505]
3. Aida H, Takakuwa K, Nagata H, Tsuneki I, Takano M, Tsuji S, Takahashi T, Sonoda T, Hatae M, Takahashi K, Hasegawa K, Mizunuma H, Toyoda N, Kamata H, Torii Y, Saito N, Tanaka K, Yakushiji M, Araki T, Tanaka K. Clinical features of ovarian cancer in Japanese women with germ-line mutations of BRCA1. Clin Cancer Res. 1998;4(1):235–40. [PubMed: 9516977]
4. Ansquer Y, Gautier C, Fourquet A, Asselain B, Stoppa-Lyonnet D. Survival in early-onset BRCA1 breast-cancer patients, Institut Curie breast cancer group. Lancet. 1998;352:541. [PubMed: 9716060]
5. Antoniou A, Pharoah PDP, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, Pasini B, Radice P, Manoukian S, Eccles DM, Tang N, Olah E, Anton-Culver H, Warner E, Lubinski J, Gronwald J, Gorski B. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 222 studies. Am J Hum Genet. 2003;72:1117–30. [PMC free article: PMC1180265] [PubMed: 12677558]
6. Antoniou AC, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL. et al. Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies. J Med Genet. 2005;42:602–603. [PMC free article: PMC1736090] [PubMed: 15994883]
7. Antoniou AC, Pharoah PP, Smith P, Easton DF. The BOADICEA model of genetic susceptibility to breast and ovarian cancer. Br J Cancer. 2004;91:1580–1590. [PMC free article: PMC2409934] [PubMed: 15381934]
8. Antoniou AC, Spurdle AB, Sinilnikova OM, Healey S, Pooley KA, Schmutzler RK, Versmold B, Engel C, Meindl A, Arnold N, Hofmann W, Sutter C, Niederacher D, Deissler H, Caldes T, Kämpjärvi K, Nevanlinna H, Simard J, Beesley J, Chen X. Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers. Am J Hum Genet. 2008;82(4):937–48. [PMC free article: PMC2427217] [PubMed: 18355772]
9. American Society of Clinical Oncology. Recommended breast cancer surveillance guidelines. Available online. 1997. Accessed 3-26-13.
10. American Society of Clinical Oncology. American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility (pdf). Available online. 2003. Accessed 3-26-13.
11. Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, Hortobagyi GN, Arun BK. Clinical and pathological characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 2008;26:4282–4288. [PubMed: 18779615]
12. Athma P, Rappaport R, Swift M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet. 1996;92:130–4. [PubMed: 8976369]
13. Aziz S, Kuperstein G, Rosen B, Cole D, Nedelcu R, McLaughlin J, Narod SA. A genetic epidemiological study of carcinoma of the fallopian tube. Gynecol Oncol. 2001;80(3):341–5. [PubMed: 11263928]
14. Beiner ME, Finch A, Rosen B, Lubinski J, Moller P, Ghadirian P, Lynch HT, Friedman E, Sun P, Narod SA. Hereditary Ovarian Cancer Clinical Study Group; The risk of endometrial cancer in women with BRCA1 and BRCA2 mutations. A prospective study. Gynecol Oncol. 2007;104(1):7–10. [PubMed: 16962648]
15. Berchuck A, Heron KA, Carney ME, Lancaster JM, Fraser EG, Vinson VL, Deffenbaugh AM, Miron A, Marks JR, Futreal PA, Frank TS. Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res. 1998;4:2433–7. [PubMed: 9796975]
16. Berman DB, Costalas J, Schultz DC, Grana G, Daly M, Godwin AK. A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res. 1996;56:3409–14. [PubMed: 8758903]
17. Bernstein JL, Bernstein L, Thompson WD, Lynch CF, Malone KE, Teitelbaum SL, Olsen JH, Anton-Culver H, Boice JD, Rosenstein BS, Borresen-Dale AL, Gatti RA, Concannon P, Haile RW. WECARE Study Collaborative Group; ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer. Br J Cancer. 2003;89:1513–6. [PMC free article: PMC2394328] [PubMed: 14562025]
18. Bernstein JL, Teraoka SN, John EM, Andrulis IL, Knight JA, Lapinski R, Olson ER, Wolitzer AL, Seminara D, Whittemore AS, Concannon P. The CHEK2*1100delC allelic variant and risk of breast cancer: screening results from the breast cancer family registry. Cancer Epidemiol Biomarkers Prev. 2006;15:348–52. [PubMed: 16492927]
19. Bertwistle D, Swift S, Marston NJ, Jackson LE, Crossland S, Crompton MR, Marshall CJ, Ashworth A. Nuclear location and cell cycle regulation of the BRCA2 protein. Cancer Res. 1997;57:5485–8. [PubMed: 9407955]
20. Biggs PJ, Bradley A. A step toward genotype-based therapeutic regimens for breast cancer in patients with BRCA2 mutations? J Natl Cancer Inst. 1998;90:951–3. [PubMed: 9665137]
21. Boddy MN, Freemont PS, Borden KL. The p53-associated protein MDM2 contains a newly characterized zinc-binding domain called the RING finger. Trends Biochem Sci. 1994;19:198–9. [PubMed: 8048160]
22. Bork P, Hofmann K, Bucher P, Neuwald AF, Altschul SF, Koonin EV. A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J. 1997;11:68–76. [PubMed: 9034168]
23. Breast Cancer Linkage Consortium; Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:1310–1316. [PubMed: 10433620]
24. Brekelmans CT, Tilanus-Linthorst MM, Seynaeve C. et al. Tumor characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2- BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer. 2007;43(5):867–876. [PubMed: 17307353]
25. Brekelmans CTM, Seynaeve C, Menke-Pluymers M, Bruggenwirth HT, Tilanus-Linthorst MMA, Bartels CCM, Kriege M, van Geel AN, Crepin CMG, Blom JC, Meijers-Heijboer H, Kliijn GM. Survival and prognostic factors in BRCA1-associated breast cancer. Annals of Oncology. 2006;17:391–400. [PubMed: 16322115]
26. Bretsky P, Haiman CA, Gilad S, Yahalom J, Grossman A, Paglin S, Van Den Berg D, Kolonel LN, Skaliter R, Henderson BE. The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort. Cancer Epidemiol Biomarkers Prev. 2003;12:733–8. [PubMed: 12917204]
27. Brodie SG, Deng CX. BRCA1-associated tumorigenesis: what have we learned from knockout mice? Trends Genet. 2001;17:S18–22. [PubMed: 11585672]
28. Brose MS, Rebbeck TR, Calzone KA, Stopfer JE, Nathanson KL, Weber BL. Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst. 2002;94(18):1365–1372. [PubMed: 12237282]
29. Brugarolas J, Jacks T. Double indemnity: p53, BRCA and cancer. p53 mutation partially rescues developmental arrest in Brca1 and Brca2 null mice, suggesting a role for familial breast cancer genes in DNA damage repair. Nat Med. 1997;3:721–2. [PubMed: 9212093]
30. Brunet JS, Narod SA, Tonin P, Foulkes WD. BRCA1 mutations and survival in women with ovarian cancer. N Engl J Med. 1997;336:1256. [PubMed: 9121524]
31. Budroni M, Cesaraccio R, Coviello V, Sechi O, Pirino D, Cossu A, Tanda F, Pisano M, Palomba G, Palmieri G. Role of BRCA2 mutation status on overall survival among breast cancer patients from Sardinia. BMC Cancer. 2009;9:62. [PMC free article: PMC2653541] [PubMed: 19232099]
32. Buller RE, Shahin MS, Geisler JP, Zogg M, De Young BR, Davis CS. Failure of BRCA1 dysfunction to alter ovarian cancer survival. Clin Cancer Res. 2002;8:1196–202. [PubMed: 12006538]
33. Burke W, Daly M, Garber J, Botkin J, Kahn MJ, Lynch P, McTiernan A, Offit K, Perlman J, Petersen G, Thomson E, Varricchio C. Recommendations for follow-up care of individuals with an inherited predisposition to cancer. II. BRCA1 and BRCA2. Cancer Genetics Studies Consortium. JAMA. 1997;277(12):997–1003. [PubMed: 9091675]
34. Byrd LM, Shenton A, Maher ER, Woodward E, Belk R, Lim C, Lalloo F, Howell A, Jayson GC, Evans GD. Better life expectancy in women with BRCA2 compared with BRCA1 mutations is attributable to lower frequency and later onset of ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:1535–42. [PubMed: 18559571]
35. Callebaut I, Mornon JP. From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair. FEBS Lett. 1997;400:25–30. [PubMed: 9000507]
36. Carlson JW, Miron A, Jarboe EA, Parast MM, Hirsch MS, Lee Y, Muto MG, Kindelberger D, Crum CP. Serous tubal intraepithelial carcinoma: its potential role in primary peritoneal serous carcinoma and serous cancer prevention. J Clin Oncol. 2008;26:4160–5. [PMC free article: PMC2654373] [PubMed: 18757330]
37. Casey MJ, Synder C, Bewtra C, Narod SA, Watson P, Lynch HT. Intra-abdominal carcinomatosis after prophylactic oophorectomy in women of hereditary breast ovarian cancer syndrome kindreds associated with BRCA1 and BRCA2 mutations. Gynecologic Oncology. 2005;97:457–67. [PubMed: 15863145]
38. Chapman MS, Verma IM. Transcriptional activation by BRCA1. Nature. 1996;382:678–9. [PubMed: 8751436]
39. CHEK2 Breast Cancer Case-Control Consortium; CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies. Am J Hum Genet. 2004;74:1175–82. [PMC free article: PMC1182081] [PubMed: 15122511]
40. Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R. Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell. 1998a;2:317–28. [PubMed: 9774970]
41. Chen PL, Chen CF, Chen Y, Xiao J, Sharp ZD, Lee WH. The BRC repeats in BRCA2 are critical for RAD51 binding and resistance to methyl methanesulfonate treatment. Proc Natl Acad Sci U S A. 1998b;95:5287–92. [PMC free article: PMC20253] [PubMed: 9560268]
42. Chen S, Iversen ES, Friebel T, Finkelstein D, Weber BL, Eisen A, Peterson LE, Schildkraut JM, Isaacs C, Peshkin BN, Corio C, Leondaridis L, Tomlinson G, Dutson D, Kerber R, Amos CI, Strong LC, Berry DA, Euhus DM, Parmigiani G. Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol. 2006;24:863–71. [PMC free article: PMC2323978] [PubMed: 16484695]
43. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25:1329–33. [PMC free article: PMC2267287] [PubMed: 17416853]
44. Chen Y, Farmer AA, Chen CF, Jones DC, Chen PL, Lee WH. BRCA1 is a 220-kDa nuclear phosphoprotein that is expressed and phosphorylated in a cell cycle-dependent manner. Cancer Res. 1996;56:3168–72. [PubMed: 8764100]
45. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, Cummings M, Nyholt D, Jenkins MA, Scott C, Pupo GM, Dork T, Bendix R, Kirk J, Tucker K, McCredie MR, Hopper JL, Sambrook J, Mann GJ, Khanna KK. Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst. 2002;94:205–15. [PubMed: 11830610]
46. Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S. Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol. 2008;26:20–5. [PubMed: 18165636]
47. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Thomson CA, Khandekar J, Petrovitch H, McTiernan A. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003;289:3243–53. [PubMed: 12824205]
48. Clarke-Pearson DL. Screening for ovarian cancer. N Engl J Med. 2009;361:170–7. [PubMed: 19587342]
49. Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetics attributable risk of breast and ovarian cancer. Cancer. 1996;77:2318–24. [PubMed: 8635102]
50. Concannon P. ATM heterozygosity and cancer risk. Nat Genet. 2002;32:89–90. [PubMed: 12205473]
51. Connor F, Bertwistle D, Mee PJ, Ross GM, Swift S, Grigorieva E, Tybulewicz VL, Ashworth A. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet. 1997;17:423–30. [PubMed: 9398843]
52. Cousineau I, Abaji C, Belmaaza A. BRCA1 regulates RAD51 function in response to DNA damage and suppresses spontaneous sister chromatid replication slippage: implications for sister chromatid cohesion, genome stability, and carcinogenesis. Cancer Res. 2005;65:11384–391. [PubMed: 16357146]
53. Crum CP, Drapkin R, Kindelberger D, Medeiros F, Miron A, Lee Y. Lessons from BRCA: the tubal fimbria emerges as an origin for pelvic serous cancer. Clinical Medicine & Research. 2007;5:35–44. [PMC free article: PMC1855333] [PubMed: 17456833]
54. Cybulski C, Górski B, Gronwald J, Huzarski T, Byrski T, Debniak T, Jakubowska A, Wokołorczyk D, Gliniewicz B, Sikorski A, Stawicka M, Godlewski D, Kwias Z, Antczak A, Krajka K, Lauer W, Sosnowski M, Sikorska-Radek P, Bar K, Klijer R, Romuald Z, Małkiewicz B, Borkowski A, Borkowski T, Szwiec M, Posmyk M, Narod SA, Lubiński J. BRCA1 mutations and prostate cancer in Poland. Eur J Cancer Prev. 2008;17:62–6. [PubMed: 18090912]
55. Cybulski C, Gorski B, Huzarski T, Masojc B, Mierzejewski M, Debniak T, Teodorczyk U, Byrski T, Gronwald J, Matyjaskik J, Zlowocka E, Lenner M, Grabowska E, Nej K, Castaneda J, Medrek K, Szymanska A, Szymanska J, Kurzawski G, Suchy J, Oszurek O, Witek A, Narod SA, Lubinski J. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75:1131–5. [PMC free article: PMC1182149] [PubMed: 15492928]
56. Daly MB, Axilbund JE, Buys S, Crawford B, Farrell CD, Friedman S, Garber JE, Goorha S, Gruber SB, Hampel H, Kaklamani V, Kohlmann W, Kurian W, Litton J, Marcom PK, Nussbaum R, Offit K, Pal Y, Pasche B, Pilarski R, Reiser W, Shannon KM, Smith JR, Swisher E, Weitzel JN. Genetic/familial high-risk assessment: breast and ovarian. Journal of the National Comprehensive Cancer Network. 2010;8:562–94. [PubMed: 20495085]
57. Daly PA, Nolan C, Green A, Ormiston W, Cody N, McDevitt T. Predictive testing for BRCA1 and 2 mutations: a male contribution. Ann Oncol. 2003;14:549–53. [PubMed: 12649099]
58. Deng CX. Tumor formation in Brca1 conditional mutant mice. Environ Mol Mutagen. 2002;39:171–7. [PubMed: 11921186]
59. Deng CX. BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Research. 2006;34:1416–26. [PMC free article: PMC1390683] [PubMed: 16522651]
60. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol. 1994;66:S177–82. [PubMed: 7836845]
61. Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995;56:265–71. [PMC free article: PMC1801337] [PubMed: 7825587]
62. Eisen A, Lubinski J, Gronwald J, Moller P, Lynch HT, Klijn J, Kim-Sing C, Neuhausen SL, Gilbert L, Ghadirian P, Manoukian S, Rennert G, Friedman E, Isaacs C, Rosen E, Rosen B, Daly M, Sun P, Narod SA. Hereditary Breast Cancer Clinical Study Group; Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst. 2008;100:1361–7. [PMC free article: PMC2556701] [PubMed: 18812548]
63. Evans DG, Eccles DM, Rahman N, Young K, Bulman M, Amir E, Shenton A, Howell A, Lalloo F. A new scoring system for the chances of identifying a BRCA1/2 mutation outperforms existing models including BRCAPRO. J Med Genet. 2004;41:474–80. [PMC free article: PMC1735807] [PubMed: 15173236]
64. Farmer H, McCabe N, Lord CJ, Tuutt ANJ, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NMB, Jackson SP, Smith GC, Ashworth A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434:917–21. [PubMed: 15829967]
65. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet. 2006;367:595–604. [PubMed: 16488803]
66. Ferla R, Calò V, Cascio S, Rinaldi G, Badalamenti G, Carreca I, Surmacz E, Colucci G, Bazan V, Russo A. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007;18 Suppl 6:vi93–8. [PubMed: 17591843]
67. Finch A, Beiner M, Lubinski J, Lynch HT, Moller P, Rosen B, Murphy J, Ghadirian P, Friedman E, Foulkes WD, Kim-Sing C, Wagner T, Tung N, Couch F, Stoppa-Lyonnet D, Ainsworth P, Daly M, Pasini B, Gershoni-Baruch R, Eng C, Olopade OI, McLennan J, Karlan B, Weitzel J, Sun P, Narod SA. Hereditary Ovarian Cancer Clinical Study Group; Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA. 2006;296:185–92. [PubMed: 16835424]
68. Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, Vogel V, Robidoux A, Dimitrov N, Atkins J, Daly M, Wieand S, Tan-Chiu E, Ford L, Wolmark N. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst. 1998;90:1371–88. [PubMed: 9747868]
69. FitzGerald MG, Bean JM, Hegde SR, Unsal H, MacDonald DJ, Harkin DP, Finkelstein DM, Isselbacher KJ, Haber DA. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet. 1997;15:307–10. [PubMed: 9054948]
70. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet. 1994;343:692–5. [PubMed: 7907678]
71. Foulkes WD, Metcalfe K, Sun P, Hanna WM, Lynch HT, Ghadirian P, Tung N, Olopade OI, Weber BL, McLennan J, Olivotto IA, Bégin LR, Narod SA. Estrogen receptor status in BRCA1- and BRCA2-related breast cancer: the influence of age, grade, and histological type. Clin Cancer Res. 2004;10:2029–34. [PubMed: 15041722]
72. Foulkes WD, Stefansson IM, Chappuis PO, Bégin LR, Goffin JR, Wong N, Trudel M, Akslen LA. Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 2003;95:1482–5. [PubMed: 14519755]
73. Foulkes WD, Wong N, Brunet JS, Begin LR, Zhang JC, Martinez JJ, Rozen F, Tonin PN, Narod SA, Karp SE, Pollak MN. Germ-line BRCA1 mutation is an adverse prognostic factor in Ashkenazi Jewish women with breast cancer. Clin Cancer Res. 1997;3:2465–9. [PubMed: 9815648]
74. Frank TS, Deffenbaugh AM, Reid JE, Hulick M, Ward BE, Lingenfelter B, Gumpper KL, Scholl T, Tavtigian SV, Pruss DR, Critchfield GC. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480–90. [PubMed: 11896095]
75. Gaffney DK, Brohet RM, Lewis CM, Holden JA, Buys SS, Neuhausen SL, Steele L, Avizonis V, Stewart JR, Cannon-Albright LA. Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations. Radiother Oncol. 1998;47:129–36. [PubMed: 9683359]
76. Gail MH, Costantino JP, Bryant J, Croyle R, Freedman L, Helzlsouer K, Vogel V. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst. 1999;91:1829–46. [PubMed: 10547390]
77. Gatti RA, Becker-Catania S, Chun HH, Sun X, Mitui M, Lai CH, Khanlou N, Babaei M, Cheng R, Clark C, Huo Y, Udar NC, Iyer RK. The pathogenesis of ataxia-telangiectasia. Learning from a Rosetta Stone. Clin Rev Allergy Immunol. 2001;20:87–108. [PubMed: 11269230]
78. Geller G, Botkin JR, Green MJ, Press N, Biesecker BB, Wilfond B, Grana G, Daly MB, Schneider K, Kahn MJ. Genetic testing for susceptibility to adult-onset cancer. The process and content of informed consent. JAMA. 1997;277:1467–74. [PubMed: 9145720]
79. Geoffroy-Perez B, Janin N, Ossian K, Lauge A, Croquette MF, Griscelli C, Debre M, Bressac-de-Paillerets B, Aurias A, Stoppa-Lyonnet D, Andrieu N. Cancer risk in heterozygotes for ataxia-telangiectasia. Int J Cancer. 2001;93:288–93. [PubMed: 11410879]
80. Ghadirian P, Lubinski J, Lynch H, Neuhausen SL, Weber B, Isaacs C, Baruch RG, Randall S, Ainsworth P, Friedman E, Horsman D, Tonin P, Foulkes WD, Tung N, Sun P, Narod SA. Smoking and the risk of breast cancer among carriers of BRCA mutations. Int J Cancer. 2004;110:413–6. [PubMed: 15095307]
81. Giusti RM, Rutter JL, Duray PH, Freedman LS, Konichezky M, Fisher-Fischbein J, Greene MH, Maslansky B, Fischbein A, Gruber SB, Rennert G, Ronchetti RD, Hewitt SM, Struewing JP, Iscovich J. A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet. 2003;40:787–92. [PMC free article: PMC1735297] [PubMed: 14569130]
82. Gowen LC, Avrutskaya AV, Latour AM, Koller BH, Leadon SA. BRCA1 required for transcription-coupled repair of oxidative DNA damage. Science. 1998;281:1009–12. [PubMed: 9703501]
83. Gruber SB, Petersen GM. Cancer risks in BRCA1 carriers: time for the next generation of studies. J Natl Cancer Inst. 2002;94:1344–5. [PubMed: 12237273]
84. Gudas JM, Li T, Nguyen H, Jensen D, Rauscher FJ, Cowan KH. Cell cycle regulation of BRCA1 messenger RNA in human breast epithelial cells. Cell Growth Differ. 1996;7:717–23. [PubMed: 8780885]
85. Haffty BG, Harrold E, Khan AJ. et al. Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status. Lancet. 2002;359:1471–7. [PubMed: 11988246]
86. Haffty BG, Silber A, Matloff E, Chung J, Lannin D. Racial differences in the incidence of BRCA1 and BRCA2 mutations in a cohort of early onset breast cancer patients:African American compared to white women. J Med Genet. 2006;43:133–7. [PMC free article: PMC2564628] [PubMed: 15983021]
87. Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, Gerdes B, Kress R, Ziegler A, Raeburn JA, Campra D, Grutzmann R, Rehder H, Rothmund M, Schmiegel W, Neoptolemos JP, Bartsch DK. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst. 2003;95:214–21. [PubMed: 12569143]
88. Hakem R, de la Pompa JL, Sirard C, Mo R, Woo M, Hakem A, Wakeham A, Potter J, Reitmair A, Billia F, Firpo E, Hui CC, Roberts J, Rossant J, Mak TW. The tumor suppressor gene Brca1 is required for embryonic cellular proliferation in the mouse. Cell. 1996;85:1009–23. [PubMed: 8674108]
89. Hartmann LC, Schaid DJ, Woods JE, Crotty TP, Myers JL, Arnold PG, Petty PM, Sellers TA, Johnson JL, McDonnell SK, Frost MH, Jenkins RB. Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med. 1999;340:77–84. [PubMed: 9887158]
90. Hartmann LC, Sellers TA, Schaid DJ, Frank TS, Soderberg CL, Sitta DL, Frost MH, Grant CS, Donohue JH, Woods JE, McDonnell SK, Vockley CW, Deffenbaugh A, Couch FJ, Jenkins RB. Efficacy of bilateral prophylactic mastectomy in BRCA1 and BRCA2 gene mutation carriers. J Natl Cancer Inst. 2001;93:1633–7. [PubMed: 11698567]
91. Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King MC, Jensen RA. Growth retardation and tumour inhibition by BRCA1. Nat Genet. 1996;12:298–302. [PubMed: 8589721]
92. Hopper JL, Southey MC, Dite GS, Jolley DJ, Giles GG, McCredie MR. et al. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999;8:741–7. [PubMed: 10498392]
93. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, D'Andrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002;297:606–9. [PubMed: 12065746]
94. Jazaeri AA, Yee CJ, Sotiriou C, Brantley KR, Boyd J, Liu ET. Gene expression profiles of BRCA1-linked, BRCA2-linked, and sporadic ovarian cancers. J Natl Cancer Inst. 2002;94:990–1000. [PubMed: 12096084]
95. Jernstrom H, Lubinski J, Lynch HT, Ghadirian P, Neuhausen S, Isaacs C, Weber BL, Horsman D, Rosen B, Foulkes WD, Friedman E, Gershoni-Baruch R, Ainsworth P, Daly M, Garber J, Olsson H, Sun P, Narod SA. Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2004;96:1094–8. [PubMed: 15265971]
96. Johannsson OT, Ranstam J, Borg A, Olsson H. Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol. 1998;16:397–404. [PubMed: 9469321]
97. John EM, Miron A, Gong G, Phipps AI, Felberg A, Li FP, West DW, Whittemore AS. Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups. JAMA. 2007;298:2869–76. [PubMed: 18159056]
98. Kauff ND, Domchek SM, Friebel TM, Robson ME, Lee J, Garber JE, Isaacs C, Evans DG, Lynch H, Eeles RA, Neuhausen SL, Daly MB, Matloff E, Blum JL, Sabbatini P, Barakat RR, Hudis C, Norton L, Offit K, Rebbeck TR. Risk-reducing salpingo-oophorectomy for the prevention of BRCA1- and BRCA2-associated breast and gynecologic cancer: a multicenter, prospective study. J Clin Oncol. 2008;26:1331–7. [PMC free article: PMC3306809] [PubMed: 18268356]
99. Kauff ND, Satagopan JM, Robson ME, Scheuer L, Hensley M, Hudis CA, Ellis NA, Boyd J, Borgen PI, Barakat RR, Norton L, Castiel M, Nafa K, Offit K. Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346:1609–15. [PubMed: 12023992]
100. King MC, Marks JH, Mandell JB. New York Breast Cancer Study Group; Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003;302:643–6. [PubMed: 14576434]
101. King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K, Tait J, Ford L, Dunn BK, Costantino J, Wickerham L, Wolmark N, Fisher B. National Surgical Adjuvant Breast and Bowel Project; Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA. 2001;286:2251–6. [PubMed: 11710890]
102. Kriege M, Brekelmans CT, Boetes C, Besnard PE, Zonderland HM, Obdeijn IM, Manoliu RA, Kok T, Peterse H, Tilanus-Linthorst MM, Muller SH, Meijer S, Oosterwijk JC, Beex LV, Tollenaar RA, de Koning HJ, Rutgers EJ, Klijn JG. Magnetic Resonance Imaging Screening Study Group; Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition. N Engl J Med. 2004;351:427–37. [PubMed: 15282350]
103. Kriege M, Seynaeve C, Meijers-Heijboer H. et al. Sensitivity to first-line chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2009;27:3764–71. [PubMed: 19564533]
104. Lacroix M, Leclercq G. The "portrait" of hereditary breast cancer. Breast Cancer Res Treat. 2005;89:297–304. [PubMed: 15754129]
105. Lafarge S, Sylvain V, Ferrara M, Bignon Y. Inhibition of BRCA1 leads to increased chemoresistance to microtubule-interfering agents, an effect that involves the JNK pathway. Oncogene. 2001;20:6597–606. [PubMed: 11641785]
106. Lakhani SR, Reis-Filho JS, Fulford L, Penault-Llorca F, van der Vijver M, Parry S, Bishop T, Benitez J, Rivas C, Bignon YJ, Chang-Claude J, Hamann U, Cornelisse CJ, Devilee P, Beckmann MW, Nestle-Krämling C, Daly PA, Haites N, Varley J, Lalloo F, Evans G, Maugard C, Meijers-Heijboer H, Klijn JG, Olah E, Gusterson BA, Pilotti S, Radice P, Scherneck S, Sobol H, Jacquemier J, Wagner T, Peto J, Stratton MR, McGuffog L, Easton DF. Breast Cancer Linkage Consortium; Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res. 2005;11:5175–80. [PubMed: 16033833]
107. Lee JS, Wacholder S, Struewing JP, McAdams M, Pee D, Brody LC, Tucker MA, Hartge P. Survival after breast cancer in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 1999;91:259–63. [PubMed: 10037104]
108. Leeper K, Garcia R, Swisher E. et al. Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol Oncol. 2002;87:52–6. [PubMed: 12468342]
109. Leide A, Narod SA. Hereditary breast and ovarian cancer in Asia: genetic epidemiology of BRCA1 and BRCA2. Hum Mutat. 2002;20:413–424. [PubMed: 12442265]
110. Levy-Lahad E, Lahad A, Eisenberg S, Dagan E, Paperna T, Kasinetz L, Catane R, Kaufman B, Beller U, Renbaum P, Gershoni-Baruch R. A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers. Proc Natl Acad Sci U S A. 2001;98:3232–6. [PMC free article: PMC30636] [PubMed: 11248061]
111. Lim W, Hearle N, Shah B, Murday V, Hodgson SV, Lucassen A, Eccles D, Talbot I, Neale K, Lim AG, O'Donohue J, Donaldson A, Macdonald RC, Young ID, Robinson MH, Lee PW, Stoodley BJ, Tomlinson I, Alderson D, Holbrook AG, Vyas S, Swarbrick ET, Lewis AA, Phillips RK, Houlston RS. Further observations on LKB1/STK11 status and cancer risk in Peutz-Jeghers syndrome. Br J Cancer. 2003;89:308–13. [PMC free article: PMC2394252] [PubMed: 12865922]
112. Lu KH, Cramer DW, Muto MG, Li EY, Niloff J, Mok SC. A population-based study of BRCA1 and BRCA2 mutations in Jewish women with epithelial ovarian cancer. Obstet Gynecol. 1999;93:34–37. [PubMed: 9916952]
113. Lubinski J, Phelan CM, Ghadirian P, Lynch HT, Garber J, Weber B, Tung N, Horsman D, Isaacs C, Monteiro AN, Sun P, Narod SA. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3:1–10. [PubMed: 15131399]
114. Ludwig T, Chapman DL, Papaioannou VE, Efstratiadis A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 1997;11:1226–41. [PubMed: 9171368]
115. Lynch HT, Deters CA, Snyder CL, Lynch JF, Villeneuve P, Silberstein J, Martin H, Narod SA, Brand RE. BRCA1 and pancreatic cancer: pedigree findings and their causal relationships. Cancer Genet Cytogenet. 2005;158:119–25. [PubMed: 15796958]
116. Marcus JN, Watson P, Page DL, Narod SA, Lenoir GM, Tonin P, Linder-Stephenson L, Salerno G, Conway TA, Lynch HT. Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer. 1996;77:697–709. [PubMed: 8616762]
117. McKinnon WC, Baty BJ, Bennett RL, Magee M, Neufeld-Kaiser WA, Peters KF, Sawyer JC, Schneider KA. Predisposition genetic testing for late-onset disorders in adults. A position paper of the National Society of Genetic Counselors. JAMA. 1997;278:1217–20. [PubMed: 9333247]
118. Medeiros F, Muto MG, Lee Y, Elvin JA, Callahan MJ, Feltmate C, Garber JE, Cramer DW, Crum CP. The tubal fimbria is a preferred site for early adenocarcinoma in women with familial ovarian cancer syndrome. Am J Surg Pathol. 2006;30:230–6. [PubMed: 16434898]
119. Metcalfe K, Lynch HT, Ghadirian P, Tung N, Olivotto I, Warner E. et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol. 2004;22:2328–35. [PubMed: 15197194]
120. Metcalfe KA, Lynch HT, Ghadirian P, Tung N, Olivotto IA, Foulkes WD, Warner E, Olopade O, Eisen A, Weber B, McLennan J, Sun P, Narod SA. The risk of ovarian cancer after breast cancer in BRCA1 and BRCA2 carriers. Gynecol Oncol. 2005a;96:222–6. [PubMed: 15589605]
121. Metcalfe KA, Snyder C, Seidel J, Hanna D, Lynch HT, Narod S. The use of preventive measures among healthy women who carry a BRCA1 or BRCA2 mutation. Fam Cancer. 2005b;4:97–103. [PubMed: 15951959]
122. Mettlin C, Jones G, Averette H, Gusberg SB, Murphy GP. Defining and updating the American Cancer Society guidelines for the cancer-related checkup: prostate and endometrial cancers. CA Cancer J Clin. 1993;43:42–6. [PubMed: 8422604]
123. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, Liu Q, Cochran C, Bennett LM, Ding W. et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994;266:66–71. [PubMed: 7545954]
124. Milne RL, Knight JA, John EM, Dite GS, Balbuena R, Ziogas A, Andrulis IL, West DW, Li FP, Southey MC, Giles GG, McCredie MR, Hopper JL, Whittemore AS. Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2005;14:350–6. [PubMed: 15734957]
125. Milner J, Ponder B, Hughes-Davies L, Seltmann M, Kouzarides T. Transcriptional activation functions in BRCA2. Nature. 1997;386:772–3. [PubMed: 9126734]
126. Monteiro AN, August A, Hanafusa H. Evidence for a transcriptional activation function of BRCA1 C-terminal region. Proc Natl Acad Sci U S A. 1996;93:13595–9. [PMC free article: PMC19361] [PubMed: 8942979]
127. Morimatsu M, Donoho G, Hasty P. Cells deleted for Brca2 COOH terminus exhibit hypersensitivity to gamma-radiation and premature senescence. Cancer Res. 1998;58:3441–7. [PubMed: 9699678]
128. Muller A, Edmonston TB, Corao DA, Rose DG, Palazzo JP, Becker H, Fry RD, Rueschoff J, Fishel R. Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res. 2002;62:1014–9. [PubMed: 11861375]
129. Naderi A, Couch FJ. BRCA2 and pancreatic cancer. Int J Gastrointest Cancer. 2002;31:99–106. [PubMed: 12622420]
130. Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL, Stoppa-Lyonnet D, Lerman C, Pasini B, de los Rios P, Weber B, Lynch H. Hereditary Breast Cancer Clinical Study Group; Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet. 2000;356:1876–81. [PubMed: 11130383]
131. Narod SA, Ford D, Devilee P, Barkardottir RB, Lynch HT, Smith SA, Ponder BA, Weber BL, Garber JE, Birch JM. et al. An evaluation of genetic heterogeneity in 145 breast-ovarian cancer families. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995;56:254–64. [PMC free article: PMC1801289] [PubMed: 7825586]
132. National Comprehensive Cancer Network. Clinical practice guidelines in oncology, genetic/familial high-risk assessment: breast and ovarian. Available at: www​.nccn.org (registration required). 2010.
133. Oddoux C, Struewing JP, Clayton CM, Neuhausen S, Brody LC, Kaback M, Haas B, Norton L, Borgen P, Jhanwar S, Goldgar D, Ostrer H, Offit K. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet. 1996;14:188–90. [PubMed: 8841192]
134. Offit K, Gilewski T, McGuire P, Schluger A, Hampel H, Brown K, Swensen J, Neuhausen S, Skolnick M, Norton L, Goldgar D. Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet. 1996;347:1643–5. [PubMed: 8642955]
135. Olivier RI, van Beurden M, Lubsen MA, Rookus MA, Mooij TM, van de Vijver MJ, van't Veer LJ. Clinical outcome of prophylactic oophorectomy in BRCA1/BRCA2 mutation carriers and events during follow-up. Br J Cancer. 2004;90:1492–7. [PMC free article: PMC2409718] [PubMed: 15083174]
136. Olopade OI, Artioli G. Efficacy of risk-reducing salpingo-oophorectomy in women with BRCA-1 and BRCA-2 mutations. Breast J. 2004;10 Suppl 1:S5–9. [PubMed: 14984481]
137. Olopade OI, Fackenthal JD, Dunston G, Tainsky MA, Collins F, Whitfield-Broome C. Breast cancer genetics in African Americans. Cancer. 2003;97 suppl 1:236–45. [PubMed: 12491487]
138. Olsen JH, Hahnemann JM, Borresen-Dale AL, Brondum-Nielsen K, Hammarstrom L, Kleinerman R, Kaariainen H, Lonnqvist T, Sankila R, Seersholm N, Tretli S, Yuen J, Boice JD, Tucker M. Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. J Natl Cancer Inst. 2001;93:121–7. [PubMed: 11208881]
139. Ouchi T, Monteiro AN, August A, Aaronson SA, Hanafusa H. BRCA1 regulates p53-dependent gene expression. Proc Natl Acad Sci U S A. 1998;95:2302–6. [PMC free article: PMC19327] [PubMed: 9482880]
140. Pal T, Permuth-Wey J, Kapoor R, Cantor A, Sutphen R. Improved survival in BRCA2 carriers with ovarian cancer. Familial Cancer. 2007;6:113–9. [PMC free article: PMC3303221] [PubMed: 17160431]
141. Parmigiani G, Berry D, Aguilar O. Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet. 1998;62:145–58. [PMC free article: PMC1376797] [PubMed: 9443863]
142. Petersen GM, Hruban RH. Familial pancreatic cancer—where are we in 2003? J Natl Cancer Inst. 2003;95:180–1. [PubMed: 12569133]
143. Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drusedau M, Hogervorst FB, Hageman S, Arts PJ, Ligtenberg MJ, Meijers-Heijboer H, Klijn JG, Vasen HF, Cornelisse CJ, van't Veer LJ, Bakker E, van Ommen GJ, Devilee P. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet. 1997;17:341–5. [PubMed: 9354803]
144. Pharoah PD, Easton DF, Stockton DL, Gayther S, Ponder BA. Survival in familial, BRCA1-associated, and BRCA2-associated epithelial ovarian cancer. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) Familial Ovarian Cancer Study Group. Cancer Res. 1999;59:868–71. [PubMed: 10029077]
145. Pierce L. Radiotherapy for breast cancer in BRCA1/BRCA2 carriers: clinical issues and management dilemmas. Semin Radiat Oncol. 2002;12:352–61. [PubMed: 12382193]
146. Pierce LJ, Levin AM, Rebbeck TR, Ben-David MA, Friedman E, Solin LJ, Harris EE, Gaffney DK, Haffty BG, Dawson LA, Narod SA, Olivotto IA, Eisen A, Whelan TJ, Olopade OI, Isaacs C, Merajver SD, Wong JS, Garber JE, Weber BL. Ten-year multi-institutional results of breast-conserving surgery and radiotherapy in BRCA1.2-associated stage I/II breast cancer. J Clin Oncol. 2006;24:2437–43. [PubMed: 16636335]
147. Piver MS, Jishi MF, Tsukada Y, Nava G. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer. A report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer. 1993;71:2751–5. [PubMed: 8467455]
148. Porter DE, Cohen BB, Wallace MR, Smyth E, Chetty U, Dixon JM, Steel CM, Carter DC. Breast cancer incidence, penetrance and survival in probable carriers of BRCA1 gene mutation in families linked to BRCA1 on chromosome 17q12-21. Br J Surg. 1994;81:1512–5. [PubMed: 7820489]
149. Powell CB, Kenley E, Chen LM, Crawford B, McLennan J, Zaloudek C, Komaromy M, Beattie M, Ziegler J. Risk-reducing salpingo-oophorectomy in BRCA mutation carriers: role of serial sectioning in the detection of occult malignancy. J Clin Oncol. 2005;23:127–32. [PubMed: 15625367]
150. Quinn JE, Kennedy RD, Mullan PB, Gilmore PM, Carty M, Johnston PG. BRCA1 functions as a differential modulator or chemotherapy-induced apoptosis. Cancer Research. 2003;63:6221–8. [PubMed: 14559807]
151. Rajan JV, Wang M, Marquis ST, Chodosh LA. Brca2 is coordinately regulated with Brca1 during proliferation and differentiation in mammary epithelial cells. Proc Natl Acad Sci U S A. 1996;93:13078–83. [PMC free article: PMC24049] [PubMed: 8917547]
152. Rakha EA, Reis-Filho JS, Ellis IO. Basal-like breast cancer: a critical review. J Clin Oncol. 2008;26:2568–81. [PubMed: 18487574]
153. Ramus SJ, Fishman A, Pharoah PD, Yarkoni S, Altaras M, Ponder BA. Ovarian cancer survival in Ashkenazi Jewish patients with BRCA1 and BRCA2 mutations. Eur J Surg Oncol. 2001;27:278–81. [PubMed: 11373105]
154. Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van't Veer L, Garber JE, Evans GR, Narod SA, Isaacs C, Matloff E, Daly MB, Olopade OI, Weber BL. Bilateral prophylactic mastectomy reduces breast cancer risk in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2004;22:1055–62. [PubMed: 14981104]
155. Rebbeck TR, Friebel T, Wagner T, Lynch HT, Garber JE, Daly MB, Isaacs C, Olopade OI, Neuhausen SL, van 't Veer L, Eeles R, Evans DG, Tomlinson G, Matloff E, Narod SA, Eisen A, Domchek S, Armstrong K, Weber BL. PROSE Study Group; Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol. 2005;23:7804–10. [PubMed: 16219936]
156. Rebbeck TR, Lynch HT, Neuhausen SL, Narod SA, Van't Veer L, Garber JE, Evans G, Isaacs C, Daly MB, Matloff E, Olopade OI, Weber BL. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346:1616–22. [PubMed: 12023993]
157. Rennert G, Bisland-Naggan S, Barnett-Griness O, Bar-Joseph N, Zhang S, Rennert HS, Narod SA. Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med. 2007;357:115–23. [PubMed: 17625123]
158. Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nature Genetics. 2006;38:873–5. [PubMed: 16832357]
159. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, Tang J, Li S, Zhang S, Shaw PA, Narod SA. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst. 2006;98:1694–706. [PubMed: 17148771]
160. Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68:700–10. [PMC free article: PMC1274482] [PubMed: 11179017]
161. Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet. 1996;14:185–7. [PubMed: 8841191]
162. Robson M, Levin D, Federici M, Satagopan J, Bogolminy F, Heerdt A, Borgen P, McCormick B, Hudis C, Norton L, Boyd J, Offit K. Breast conservation therapy for invasive breast cancer in Ashkenazi women with BRCA gene founder mutations. J Natl Cancer Inst. 1999;91:2112–7. [PubMed: 10601383]
163. Robson M, Scheuer L, Nafa K, Ellis N, Offit K. Unique de novo mutation of BRCA2 in a woman with early onset breast cancer. J Med Genet. 2002;39:126–8. [PMC free article: PMC1735025] [PubMed: 11836363]
164. Robson ME, Chappuis PO, Satagopan J, Wong N, Boyd J, Goffin JR, Hudis C, Roberge D, Norton L, Bégin LR, Offit K, Foulkes WD. A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res. 2004;6:R8–R17. [PMC free article: PMC314444] [PubMed: 14680495]
165. Rosen EM, Fan S, Ma X. BRCA1 regulation of transcription. Cancer Letters. 2006;236:175–85. [PubMed: 15975711]
166. Rubin SC, Benjamin I, Behbakht K, Takahashi H, Morgan MA. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Engl J Med. 1996;335:1413–6. [PubMed: 8875917]
167. Rutter JL, Wacholder S, Chetrit A, Lubin F, Menczer J, Ebbers S, Tucker MA, Struewing JP, Hartge P. Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study. J Natl Cancer Inst. 2003;95:1072–8. [PubMed: 12865453]
168. Sabel MS. Is breast conservation the wrong choice in women with BRCA1 or BRCA2 mutations? Am J Oncol Rev. 2002;1:155–7.
169. Sankaran S, Starita LM, Simons AM, Parvin JD. Identification of domains of BRCA1 critical for the ubiquitin-dependent inhibition of centrosome function. Cancer Res. 2006;66:4100–7. [PubMed: 16618730]
170. Satagopan JM, Boyd J, Kauff ND, Robson M, Scheuer L, Narod S. et al. Ovarian cancer risk in Ashkenazi Jewish carrier of BRCA1 and BRCA2 mutations. Clin Cancer Res. 2002;8:3776–81. [PubMed: 12473589]
171. Satagopan JM, Offit K, Foulkes W, Robson M, Wacholder S, Eng C. et al. The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev. 2001;10:467–73. [PubMed: 11352856]
172. Schneider KA. Counseling About Cancer: Strategies for Genetic Counseling. 2 ed. New York, NY: Wiley-Liss; 2002.
173. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF. Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci U S A. 2002;99:925–30. [PMC free article: PMC117407] [PubMed: 11805335]
174. Seynaeve C, Verhoog LC, van de Bosch LM, van Geel AN, Menke-Pluymers M, Meijers-Heijboer EJ, van den Ouweland AM, Wagner A, Creutzberg CL, Niermeijer MF, Klijn JG, Brekelmans CT. Ipsilateral breast tumour recurrence in hereditary breast cancer following breast-conserving therapy. Eur J Cancer. 2004;40:1150–8. [PubMed: 15110878]
175. Sharan SK, Morimatsu M, Albrecht U, Lim DS, Regel E, Dinh C, Sands A, Eichele G, Hasty P, Bradley A. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 1997;386:804–10. [PubMed: 9126738]
176. Siddique H, Zou JP, Rao VN, Reddy ES. The BRCA2 is a histone acetyltransferase. Oncogene. 1998;16:2283–5. [PubMed: 9619837]
177. Smith SA, Easton DF, Evans DG, Ponder BA. Allele losses in the region 17q12-21 in familial breast and ovarian cancer involve the wild-type chromosome. Nat Genet. 1992;2:128–31. [PubMed: 1303261]
178. Somasundaram K, Zhang H, Zeng YX, Houvras Y, Peng Y, Zhang H, Wu GS, Licht JD, Weber BL, El-Deiry WS. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature. 1997;389:187–90. [PubMed: 9296497]
179. Sommer SS, Buzin CH, Jung M, Zheng J, Liu Q, Jeong SJ, Moulds J, Nguyen VQ, Feng J, Bennett WP, Dritschilo A. Elevated frequency of ATM gene missense mutations in breast cancer relative to ethnically matched controls. Cancer Genet Cytogenet. 2002;134:25–32. [PubMed: 11996792]
180. Spence CW, Judkins T, Schoenberger J, Balzotti M, Rajamani S, Colvin C, Burbidge A, Chen S, Frost M, Trost J, Wenstrup R, Roa B. Clinical testing experience for large genomic rearrangements in the BRCA1 and BRCA2 genes for hereditary breast and ovarian cancer. Poster. San Diego, CA: 57th Annual Meeting of the American Society of Human Genetics. 2007.
181. Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, Ramsay J, McKinnon PJ, Swift M, Lavin MF. Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet. 2002;32:185–90. [PubMed: 12195425]
182. Stadler ZK, Saloustros E, Hansen NAL, Schluger AE, Kauff ND, Offit K, Robson ME. Absence of genomic BRCA1 and BRCA2 rearrangements in Ashkenazi breast and ovarian cancer families. Breast Cancer Res Treat. 2010;123:581–5. [PubMed: 20221693]
183. Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P, Bedenham T, Bradwell AR, Easton DF, Lennox GG, Haites N, Byrd PJ, Taylor AM. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998;62:334–45. [PMC free article: PMC1376883] [PubMed: 9463314]
184. Stoppa-Lyonnet D, Ansquer Y, Dreyfus H. et al. Familial invasive breast cancers: worse outcome related to BRCA1 mutations. J Clin Oncol. 2000;18:4053–9. [PubMed: 11118466]
185. Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS, Brody LC. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet. 1995;11:198–200. [PubMed: 7550349]
186. Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, Timmerman MM, Brody LC, Tucker MA. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997;336:1401–8. [PubMed: 9145676]
187. Suzuki A, de la Pompa JL, Hakem R, Elia A, Yoshida R, Mo R, Nishina H, Chuang T, Wakeham A, Itie A, Koo W, Billia P, Ho A, Fukumoto M, Hui CC, Mak TW. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 1997;11:1242–52. [PubMed: 9171369]
188. Swift M, Morrell D, Massey RB, Chase CL. Incidence of cancer in 161 families affected by ataxia-telangiectasia. N Engl J Med. 1991;325:1831–6. [PubMed: 1961222]
189. Szabo CI, King MC. Population genetics of BRCA1 and BRCA2. Am J Hum Genet. 1997;60:1013–20. [PMC free article: PMC1712447] [PubMed: 9150148]
190. Tai YC, Domchek S, Parmigiani G, Chen S. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007;99:1811–4. [PMC free article: PMC2267289] [PubMed: 18042939]
191. Tan DSP, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, Ardern-Jones A, Norman A, Kaye SB, Gore ME. “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol. 2008;26:5530–6. [PubMed: 18955455]
192. Teraoka SN, Malone KE, Doody DR, Suter NM, Ostrander EA, Daling JR, Concannon P. Increased frequency of ATM mutations in breast carcinoma patients with early onset disease and positive family history. Cancer. 2001;92:479–87. [PubMed: 11505391]
193. Tesoriero A, Anderson C, Southey M, Somers G, McKay M, Armes J. et al. De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet. 1999;65:567–9. [PMC free article: PMC1377956] [PubMed: 10417300]
194. Thompson D, Easton DF. The breast cancer linkage consortium. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002;94:1358–65. [PubMed: 12237281]
195. Thorlacius S, Olafsdottir G, Tryggvadottir L, Neuhausen S, Jonasson JG, Tavtigian SV, Tulinius H, Ogmundsdottir HM, Eyfjord JE. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet. 1996;13:117–9. [PubMed: 8673089]
196. Thorlacius S, Struewing JP, Hartge P, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Wacholder S, Tulinius H, Eyfjord JE. Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. 1998;352:1337–9. [PubMed: 9802270]
197. Thorstenson YR, Roxas A, Kroiss R, Jenkins MA, Yu KM, Bachrich T, Muhr D, Wayne TL, Chu G, Davis RW, Wagner TM, Oefner PJ. Contributions of ATM mutations to familial breast and ovarian cancer. Cancer Res. 2003;63:3325–33. [PubMed: 12810666]
198. Tryggvadottir L, Vidarsdottir L, Thorgeirsson T, Jonasson JG, Olafsdottir EJ, Olafsdottir GH. et al. J Natl Cancer Inst. 2007;99:929–35. [PubMed: 17565157]
199. Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004;23:1111–30. [PubMed: 15057881]
200. Van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, Hoogerbrugge N, Verhoef S, Vasen HF. et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet. 2005;42:711–9. [PMC free article: PMC1736136] [PubMed: 16141007]
201. van der Luijt RB, van Zon PH, Jansen RP, van der Sijs-Bos CJ, Warlam-Rodenhuis CC, Ausems MG. De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer. J Med Genet. 2001;38:102–5. [PMC free article: PMC1734809] [PubMed: 11158174]
202. Vaughn JP, Cirisano FD, Huper G, Berchuck A, Futreal PA, Marks JR, Iglehart JD. Cell cycle control of BRCA2. Cancer Res. 1996;56:4590–4. [PubMed: 8840967]
203. Venkitaraman AR. Functions of BRCA1 and BRCA2 in the biological response to DNA damage. Journal of Cell Science. 2001;114:3591–8. [PubMed: 11707511]
204. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002;108:171–82. [PubMed: 11832208]
205. Verhoog LC, Brekelmans CT, Seynaeve C, Dahmen G, van Geel AN, Bartels CC, Tilanus-Linthorst MM, Wagner A, Devilee P, Halley DJ, van den Ouweland AM, Meijers-Heijboer EJ, Klijn JG. Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol. 1999;17:3396–402. [PubMed: 10550133]
206. Verhoog LC, Brekelmans CT, Seynaeve C, van den Bosch LM, Dahmen G, van Geel AN, Tilanus-Linthorst MM, Bartels CC, Wagner A, van den Ouweland A, Devilee P, Meijers-Heijboer EJ, Klijn JG. Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet. 1998;351:316–21. [PubMed: 9652611]
207. Walsh MD, Buchanan DD, Cummings MC, Pearson SA, Arnold ST, Clendenning M, Walters R, McKeone DM, Spurdle AB, Hopper JL, Jenkins MA, Phillips KD, Suthers GK, George J, Goldblatt J, Muir A, Tucker K, Pelzer E, Gattas MR, Woodall S, Parry S, Macrae FA, Haile RW, Baron JA, Potter JD, Le Marchand L, Bapat B, Thibodeau SN, Lindor NM, McGuckin MA, Young JP. Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res. 2010;16:2214–24. [PMC free article: PMC2848890] [PubMed: 20215533]
208. Warner E, Causer PA. MRI surveillance for hereditary breast-cancer risk. Lancet. 2005;365:1747–9. [PubMed: 15910935]
209. Warner E, Plewes DB, Hill KA, Causer PA, Zubovits JT, Jong RA, Cutrara MR, DeBoer G, Yaffe MJ, Messner SJ, Meschino WS, Piron CA, Narod SA. Surveillance of BRCA1 and BRCA2 mutation carriers with magnetic resonance imaging, ultrasound, mammography, and clinical breast examination. JAMA. 2004;292:1317–25. [PubMed: 15367553]
210. Weischer M, Bojesen SE, Tybjaerg-Hansen A, Axelsson CK, Nordestgaard BG. Increased risk of breast cancer associated with CHEK2*1100delC. J Clin Oncol. 2007;25:57–63. [PubMed: 16880452]
211. Whittemore AS, Balise RR, Pharoah PD, Dicioccio RA, Oakley-Girvan I, Ramus SJ, Daly M, Usinowicz MB, Garlinghouse-Jones K, Ponder BA, Buys S, Senie R, Andrulis I, John E, Hopper JL, Piver MS. Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations. Br J Cancer. 2004;91:1911–5. [PMC free article: PMC2410144] [PubMed: 15545966]
212. Whittemore AS, Gong G, Itnyre J. Prevalence and contribution of BRCA1 mutations in breast cancer and ovarian cancer: results from three U.S. population-based case-control studies of ovarian cancer. Am J Hum Genet. 1997;60:496–504. [PMC free article: PMC1712497] [PubMed: 9042908]
213. Wong AKC, Pero R, Ormonde PA, Tavtigian SV, Bartel PL. RAD51 interacts with the evolutionarily conserved BRC motifs in the human breast cancer susceptibility gene brca2. J Biol Chem. 1997;272:31941–4. [PubMed: 9405383]
214. Wu LC, Wang ZW, Tsan JT, Spillman MA, Phung A, Xu XL, Yang MC, Hwang LY, Bowcock AM, Baer R. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet. 1996;14:430–40. [PubMed: 8944023]
215. Zhang H, Tombline G, Weber BL. BRCA1, BRCA2, and DNA damage response: collision or collusion? Cell. 1998;92:433–6. [PubMed: 9491884]
216. Zweemer RP, Verheijen RH, Coebergh JW, Jacobs IJ, van Diest PJ, Gille JJ, Skates S, Menko FH, Ten Kate LP, Kenemans P. Survival analysis in familial ovarian cancer, a case control study. Eur J Obstet Gynecol Reprod Biol. 2001;98:219–23. [PubMed: 11574135]

Suggested Reading

1. Boughey JC, Hartmann LC, Anderson SS, Degnim AC, Vierkant RA, Reynolds CA, Frost MH, Pankratz VS. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol. 2010;28:3591–6. [PMC free article: PMC2917314] [PubMed: 20606088]
2. Claus EB, Risch N, Thompson WD, Carter D. Relationship between breast histopathology and family history of breast cancer. Cancer. 1993;71:147–53. [PubMed: 8380113]
3. Couch FJ, Hartmann LC. BRCA1 testing--advances and retreats. JAMA. 1998;279:955–7. [PubMed: 9544772]
4. Croyle RT, Smith KR, Botkin JR, Baty B, Nash J. Psychological responses to BRCA1 mutation testing: preliminary findings. Health Psychol. 1997;16:63–72. [PubMed: 9028816]
5. FitzGerald MG, MacDonald DJ, Krainer M, Hoover I, O'Neil E, Unsal H, Silva-Arrieto S, Finkelstein DM, Beer-Romero P, Englert C, Sgroi DC, Smith BL, Younger JW, Garber JE, Duda RB, Mayzel KA, Isselbacher KJ, Friend SH, Haber DA. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med. 1996;334:143–9. [PubMed: 8531968]
6. Frank TS, Manley SA, Olopade OI, Cummings S, Garber JE, Bernhardt B, Antman K, Russo D, Wood ME, Mullineau L, Isaacs C, Peshkin B, Buys S, Venne V, Rowley PT, Loader S, Offit K, Robson M, Hampel H, Brener D, Winer EP, Clark S, Weber B, Strong LC, Thomas A. et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998;16:2417–25. [PubMed: 9667259]
7. Garber JE, Offit K. Hereditary cancer predisposition syndromes. J Clin Oncol. 2005;23:276–92. [PubMed: 15637391]
8. Jensen RA, Thompson ME, Jetton TL, Szabo CI, van der Meer R, Helou B, Tronick SR, Page DL, King MC, Holt JT. BRCA1 is secreted and exhibits properties of a granin. Nat Genet. 1996;12:303–8. [PubMed: 8589722]
9. Lerman C, Narod S, Schulman K, Hughes C, Gomez-Caminero A, Bonney G, Gold K, Trock B, Main D, Lynch J, Fulmore C, Snyder C, Lemon SJ, Conway T, Tonin P, Lenoir G, Lynch H. BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA. 1996;275:1885–92. [PubMed: 8648868]
10. Malone KE, Daling JR, Weiss NS, McKnight B, White E, Voigt LF. Family history and survival of young women with invasive breast carcinoma. Cancer. 1996;78:1417–25. [PubMed: 8839546]
11. Narod SA, Foulkes WD. BRCA1 and BRCA2: 1994 and beyond. Nat Rev Cancer. 2004;4:665–76. [PubMed: 15343273]
12. Narod SA, Offit K. Prevention and management of hereditary breast cancer. J Clin Oncol. 2005;23:1656–63. [PubMed: 15755973]
13. Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, Hogervorst F, Brohet R, Ligtenberg MJ, Teugels E, van der Luijt R, van der Hout AH, Gille JJ, Pals G, Jedema I, Olmer R, van Leeuwen I, Newman B, Plandsoen M, van der Est M, Brink G, Hageman S, Arts PJ, Bakker MM, Devilee P. et al. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet. 1997;60:1041–9. [PMC free article: PMC1712432] [PubMed: 9150151]
14. Robson M. Breast cancer surveillance in women with hereditary risk due to BRCA1 or BRCA2 mutations. Clin Breast Cancer. 2004;5:260–8. [PubMed: 15507170]
15. Rosen PP, Lesser ML, Senie RT, Kinne DW. Epidemiology of breast carcinoma III: relationship of family history to tumor type. Cancer. 1982;50:171–9. [PubMed: 6282433]
16. Scully R, Xie A, Nagaraju G. Molecular functions of BRCA1 in the DNA damage response. Cancer Biol Ther. 2004;3:521–7. [PubMed: 15280660]
17. Shattuck-Eidens D, McClure M, Simard J, Labrie F, Narod S, Couch F, Hoskins K, Weber B, Castilla L, Erdos M. et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995;273:535–41. [PubMed: 7837387]
18. Stratton MR, Ford D, Neuhasen S, Seal S, Wooster R, Friedman LS, King MC, Egilsson V, Devilee P, McManus R. et al. Familial male breast cancer is not linked to the BRCA1 locus on chromosome 17q. Nat Genet. 1994;7:103–7. [PubMed: 8075631]
19. Struewing JP, Brody LC, Erdos MR, Kase RG, Giambarresi TR, Smith SA, Collins FS, Tucker MA. Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer. Am J Hum Genet. 1995;57:1–7. [PMC free article: PMC1801253] [PubMed: 7611277]
20. Tirkkonen M, Johannsson O, Agnarsson BA, Olsson H, Ingvarsson S, Karhu R, Tanner M, Isola J, Barkardottir RB, Borg A, Kallioniemi OP. Distinct somatic genetic changes associated with tumor progression in carriers of BRCA1 and BRCA2 germ-line mutations. Cancer Res. 1997;57:1222–7. [PubMed: 9102202]
21. Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer Sci. 2004;95:866–71. [PubMed: 15546503]

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

• 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