Features characteristic of familial, versus sporadic, breast cancer are younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men Hall et al. (1990).
According to the ... - Familial Breast Cancer Features characteristic of familial, versus sporadic, breast cancer are younger age at diagnosis, frequent bilateral disease, and frequent occurrence of disease among men Hall et al. (1990). According to the conclusions of the Breast Cancer Linkage Consortium (1997), the histology of breast cancers in women predisposed by reason of carrying BRCA1 and BRCA2 mutations differs from that in sporadic cases, and there are differences between breast cancers in carriers of BRCA1 and BRCA2 mutations. The findings were interpreted as suggesting that breast cancer due to BRCA1 has a different natural history from BRCA2 or apparently sporadic disease, which may have implications for screening and management. - Proliferative Breast Disease (PBD) In studies of 103 women from 20 kindreds that were selected for the presence of 2 first-degree relatives with breast cancer and of 31 control women, Skolnick et al. (1990) found, by 4-quadrant fine-needle breast aspirates, evidence of proliferative breast disease in 35% of clinically normal female first-degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggested that genetic susceptibility caused both PBD, a precursor lesion, and breast cancer in these kindreds. The study supported the hypothesis that this susceptibility is responsible for a considerable proportion of breast cancer, including unilateral and postmenopausal breast cancer. - Ovarian Cancer Fraumeni et al. (1975) reported 6 families with multiple cases of ovarian cancer, mainly serous cystadenocarcinoma. Breast cancer also aggregated in 3 of the 6. Prophylactic oophorectomy was performed in 14 asymptomatic women from 4 of the families. Review of the microscopic sections from 8 women showed that 3, representing 2 families, had abnormalities of ovarian surface epithelium and mesothelial tissue. Nevo (1978) described 2 families with multiple cases of ovarian papillary adenocarcinoma. In 1 family the tumor was detected in 4 females, of whom 2 had had breast cancer before the development of ovarian cancer. Among 28 women in 16 families at high risk of ovarian carcinoma, in whom prophylactic oophorectomy was performed, 3 subsequently developed disseminated intraabdominal malignancy (Tobacman et al., 1982). The primary site was uncertain despite extensive investigations, and the tumors were indistinguishable histopathologically from ovarian carcinoma. The authors concluded that in ovarian-cancer-prone families the susceptible tissue is not limited to the ovary, but includes other derivatives of the coelomic epithelium, from which primary peritoneal neoplasms may arise. Lynch et al. (1986) expanded on this hypothesis and postulated that patients with hereditary predisposition to ovarian carcinoma harbor the first germinal hit in both the epithelial cells of the ovary as well as their derivatives in the coelomic mesothelium. These patients may then be inordinately susceptible to carcinogenesis from the second, somatic, hit in these same tissues. Lynch et al. (1986) referred to the condition as 'familial peritoneal ovarian carcinomatosis.' Schildkraut et al. (1989) found a significant genetic correlation between ovarian and breast cancer. On the other hand, evidence for a significant genetic overlap between endometrial cancer (608089) and either ovarian or breast cancer was not found. In a multicenter population-based case-control study of 493 women aged 20 to 54 who had been newly diagnosed with epithelial ovarian cancer, Schildkraut and Thompson (1988) found that the odds ratios for ovarian cancer in first- and second-degree relatives were 3.6 and 2.9, respectively, compared with women with no family history of ovarian cancer. The null hypothesis of no association was excluded on both the maternal and paternal sides of the families studied. Among 310 Israeli Jewish women with ovarian cancer of epithelial origin, Menczer and Ben-Baruch (1991) found 24 distributed in 8 families with multiple cases. Of first-degree relatives of these probands, 5 underwent prophylactic oophorectomy, and early ovarian carcinoma was found in 1. Evans et al. (1992) reported a woman with ovarian cancer who developed bilateral medullary carcinoma of the breast after oophrectomy, all by age 40 years. Family history revealed 7 additional family members with ovarian cancer, 1 of whom also developed breast cancer. The mode of transmission was consistent with autosomal dominant inheritance. Twelve female family members had underwent bilateral prophylactic oophorectomy and been given hormone replacement therapy. To address whether or not there is an association between the presence of a BRCA1 mutation and the subtype of epithelial ovarian carcinoma, Narod et al. (1994) reviewed the histology of 49 ovarian cancers seen in 16 hereditary breast-ovarian cancer families shown to be linked to BRCA1 markers. Of the 49 cancers, 5 (10.2%) were mucinous. By haplotype analysis with 17q markers, they determined the BRCA1 carrier status of 40 of the cases; 36 occurred in women who were BRCA1 mutation carriers and 4 were sporadic in that they occurred in noncarriers. Only 2 of the 36 ovarian cancers found in BRCA1 carriers were mucinous, compared with 3 or 4 mucinous carcinomas observed in BRCA1 noncarriers. Liede et al. (1998) raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, 185delAG mutation of the BRCA1 gene (113705.0003) segregated with the cancer. Liede et al. (1998) concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. Patients with germline BRCA1 mutations may develop papillary serous carcinoma of the peritoneum (PSCP), a malignancy that diffusely involves peritoneal surfaces, sparing or only superficially involving the ovaries. PSCP is histologically indistinguishable from serous epithelial ovarian carcinoma, and it may develop years after oophorectomy. Schorge et al. (1998) used the androgen receptor (AR; 313700) gene locus to test the hypothesis that some cases of PSCP have a multifocal origin and to determine if patients with germline BRCA1 mutations develop multifocal PSCP. Specimens were studied from 22 women with PSCP. The AR gene locus was evaluated for patterns of loss of heterozygosity and X-chromosome inactivation. The methylation-sensitive HpaII restriction enzyme was used to differentiate the active and inactive X chromosomes. They found patterns of selective LOH at the AR locus in 5 (23%) of the 22 subjects, consistent with multifocal, polyclonal disease origin. Two patients with selective LOH also had alternating X-chromosome inactivation patterns. Patients with germline BRCA1 mutations were more likely to have evidence of multifocal disease.
In affected members of 5 of 8 kindreds with hereditary breast-ovarian cancer syndrome, Miki et al. (1994) identified 5 different heterozygous pathogenic mutations in the BRCA1 gene (see, e.g., 113705.0035). The mutations included an 11-bp deletion, a 1-bp ... In affected members of 5 of 8 kindreds with hereditary breast-ovarian cancer syndrome, Miki et al. (1994) identified 5 different heterozygous pathogenic mutations in the BRCA1 gene (see, e.g., 113705.0035). The mutations included an 11-bp deletion, a 1-bp insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. Castilla et al. (1994) found 8 putative disease-causing mutations in the BRCA1 gene (see, e.g., 113705.0001; 113705.0006; 113705.0013; 113705.0014) in 50 probands with a family history of breast and/or ovarian cancer. The authors used single-strand conformation polymorphism (SSCP) analysis on PCR-amplified genomic DNA. The data were considered consistent with a tumor suppressor model. The heterogeneity of mutations, coupled with the large size of the gene, indicated that clinical application of BRCA1 mutation testing would be technically challenging. In 10 families with breast-ovarian cancer, Friedman et al. (1994) used SSCP analysis and direct sequencing to identify 9 different heterozygous BRCA1 mutations (see, e.g., 113705.0004; 113705.0007-113705.0009). The mutations in 7 instances led to protein truncation at sites throughout the gene. A missense mutation, which occurred independently in 2 families, led to loss of a cysteine in the zinc-binding domain. An intronic single basepair substitution destroyed an acceptor site and activated a cryptic splice site, leading to a 59-bp insertion and chain termination. In 4 families with both breast and ovarian cancer, chain termination mutations were found in the N-terminal half of the protein. In a population-based series of 54 breast cancer cases from southern California, Friedman et al. (1997) found no instance of germline mutation in the BRCA1 gene but found 2 male breast cancer patients who carried novel truncating mutations in the BRCA2 gene. Only 1 of the 2 had a family history of cancer, namely, ovarian cancer in a first-degree relative. - Modifier Genes Women who carry a mutation in the BRCA1 gene have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 years. Phelan et al. (1996) demonstrated that a modifier of this risk is the HRAS1 (190020) variable number of tandem repeats (VNTR) polymorphism, located 1 kb downstream of the HRAS1 oncogene. Individuals who have rare alleles of this VNTR had been found to have an increased risk of certain types of cancer, including breast cancer. Phelan et al. (1996) claimed that this was the first study to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome. Nathanson et al. (2002) used nonparametric linkage analysis to determine whether allele sharing of chromosomes 4p, 4q, and 5q was observed preferentially within 16 BRCA1 mutation families in women with BRCA1 mutations and breast cancer. No significant linkage on chromosome 4p or 4q was observed associated with breast cancer risk in BRCA1 mutation carriers. However, the authors observed a significant linkage signal at D5S1471 on chromosome 5q (P = 0.009) in all the families analyzed together. The significance of this observation increased in the subset of families with an average of breast cancer diagnosis less than 45 years (P = 0.003). The authors suggested that one or more genes on chromosome 5q33-q34 modify breast cancer risk in BRCA1 mutation carriers. In a sample of 10,358 carriers of BRCA1 or BRCA2 gene mutations from 23 studies, Antoniou et al. (2008) observed an association between breast cancer and a SNP (dbSNP rs3803662) in the TNRC9 gene (TOX3; 611416) (per allele hazard ratio of 1.13, p(trend) = 5 x 10(-5)). The authors postulated a multiplicative effect for the SNP on breast cancer risk.
In a study of 37 families with 4 or more cases of breast cancer or breast and ovarian cancer, Friedman et al. (1995) found that 5 families of Ashkenazi Jewish descent carried ... - Ashkenazi Jewish Population In a study of 37 families with 4 or more cases of breast cancer or breast and ovarian cancer, Friedman et al. (1995) found that 5 families of Ashkenazi Jewish descent carried the BRCA1 185delAG mutation (113705.0003) and shared the same haplotype at 8 polymorphic markers spanning approximately 850 kb. Expressivity of 185delAG in these families varied from early-onset bilateral breast cancer and ovarian cancer to late-onset breast cancer without ovarian cancer. Overall, BRCA1 mutations were detected in 26 of the families: 16 with positive BRCA1 linkage lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Following the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families, Struewing et al. (1995) determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and in 815 reference persons not selected for ethnic origin. They found the 185delAG mutation in 0.9% of Ashkenazim (95% confidence limit, 0.4%-1.8%) and in none of the reference samples. The results suggested that 1 in 100 women of Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer. In an editorial, Goldgar and Reilly (1995) raised the possibility that a high frequency of mortality from breast cancer in Nassau County, New York, in the previous 2 decades might be related to the high proportion of Ashkenazim (roughly 16%) in that population; the pathogenetic collaboration of exposure to an environmental pollutant was raised. Ethical, legal, and social issues raised by these findings were also discussed. Among 5,318 Jewish subjects, Struewing et al. (1997) found 120 carriers of a BRCA1 or BRCA2 mutation. The BRCA1 mutations studied were 185delAG and 5382insC (113705.0018); the BRCA2 mutation studied was 6174delT (600185.0009). By the age of 70, the estimated risk of breast cancer among carriers was 56%; of ovarian cancer, 16%; and of prostate cancer, 16%. There were no significant differences in the risk of breast cancer between carriers of BRCA1 mutations and carriers of BRCA2 mutations, and the incidence of colon cancer among the relatives of carriers was not elevated. They concluded that over 2% of Ashkenazi Jews carried mutations in BRCA1 or BRCA2 that conferred increased risks of breast, ovarian, and prostate cancer. Krainer et al. (1997) found definite BRCA2 mutations in 2 of 73 women with early onset (by age 32) breast cancer, suggesting that BRCA2 is associated with fewer cases than BRCA1 (P = 0.03). In a series of 268 Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset, Fodor et al. (1998) determined the frequency of the common BRCA1 and BRCA2 mutations: 185delAG, 5382insC, and 6174delT. DNA was analyzed for the 3 mutations by allele-specific oligonucleotide (ASO) hybridization. Eight patients (3%) were heterozygous for the 185delAG mutation, 2 (0.75%) for the 5382insC mutation, and 8 (3%) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was estimated to be 36%, approximately 3 times the overall risk for the general population (relative risk 2.9). The results differed markedly from previous estimates based on high-risk breast cancer families. Friedman et al. (1998) pooled results from 4 cancer/genetic centers in Israel to analyze approximately 1,500 breast-ovarian cancer Ashkenazi patients for the presence of double heterozygosity as well as homozygosity for any of these mutations. Although the small number of cases precluded definite conclusions, the results suggested that the phenotypic effects of double heterozygosity for BRCA1 and BRCA2 germline mutations were not cumulative. This was in agreement with the observation that the phenotype of mice that are homozygous knockouts for the BRCA1 and BRCA2 genes is similar to that of mice that were BRCA1 knockouts. This suggests that the BRCA1 mutation is epistatic over the BRCA2 mutation. Two of the double heterozygotes described had had reproductive problems: one with primary sterility and irregular menses and another with premature menopause at the age of 37 years. In Australia, Bahar et al. (2001) found in Ashkenazi Jews the same high prevalence of 4 founder mutations as found in Ashkenazi Jews in the United States and Israel. The 4 mutations analyzed were 185delAG and 5382insC in BRCA1; 6174delT in BRCA2; and I1307K (611731.0029) in APC. King et al. (2003) determined the risks of breast and ovarian cancer for Ashkenazi Jewish women with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2. They selected 1,008 index cases, regardless of family history of cancer, and carried out molecular analysis across entire families. The lifetime risk of breast cancer among female mutation carriers was 82%, similar to risks in families with many cases. Risks appeared to be increasing with time: breast cancer risk by age 50 years among mutation carriers born before 1940 was 24%, but among those born after 1940 it was 67%. Lifetime risks of ovarian cancer were 54% for BRCA1 and 23% for BRCA2 mutation carriers. Physical exercise and lack of obesity in adolescence were associated with significantly delayed breast cancer onset. Easton et al. (2004) and Wacholder et al. (2004) disputed the conclusions of the report by King et al. (2003) estimating a breast cancer risk by age 70 to be 71%, irrespective of mutation. Both groups suggested bias of ascertainment. King (2004) rebutted these comments, suggesting that their penetrance estimates, at least to age 60, were comparable to those of other reported studies and that only the risk above age 70 was higher in their study, which may reflect a small sample size in that age group. Among 1,098 Ashkenazi Jewish women with breast and/or ovarian cancer, Kadouri et al. (2007) found that those with BRCA1 or BRCA2 founder mutations (329 patients) had a 2.5-fold increased risk of other cancers compared to those without BRCA1/2 mutations. Among specific cancers, BRCA1 carriers had a 3.9-fold increased risk for colon cancer and BRCA2 carriers had an 11.9-fold increased risk for lymphoma, the latter of which may have been related to treatment. - Other Populations Johannsson et al. (1996) identified 9 different germline mutations in the BRCA1 gene in 15 of 47 kindreds from southern Sweden, by use of SSCP and heteroduplex analysis of all exons and flanking intron region and by a protein-truncation test for exon 11, followed by direct sequencing. All but one of the mutations were predicted to give rise to premature translation termination and included 7 frameshift insertions or deletions, a nonsense mutation, and a splice acceptor site mutation. The remaining mutation was a missense mutation (cys61-to-gly) in the zinc-binding motif. They also identified 4 novel Swedish founding mutations: deletion of 2595A in 5 families, the C-to-T nonsense mutation of nt1806 in 3 families, the insertion of TGAGA after nt3166 in 3 families, and the deletion of 11 nucleotides after nt1201 in 2 families. Analysis of the intragenic polymorphism D17S855 supported common origins of the mutations. Eleven of the 15 kindreds manifesting BRCA1 mutations were breast-ovarian cancer families, several of which had a predominant ovarian cancer phenotype. Among the 32 families in which no BRCA1 alteration was detected, there was 1 breast-ovarian cancer kindred showing clear linkage to the BRCA1 region and loss of the wildtype chromosome in associated tumors. Other tumor types found in BRCA1 mutation or haplotype carriers included prostatic, pancreas, skin, and lung cancer, a malignant melanoma, an oligodendroglioma, and a carcinosarcoma. In all, 12 of the 16 kindreds manifesting BRCA1 mutation or linkage contained ovarian cancer, as compared with only 6 of the remaining 31 families. Gayther et al. (1997) found that the 5382insC and 4153delA (113705.0030) mutations in the BRCA1 gene may account for 86% of cases of familial ovarian cancer in Russia. Hamann et al. (1997) studied 45 German breast/ovarian cancer families for germline mutations in the BRCA1 gene. They identified 4 germline mutations in 3 breast cancer families and in 1 breast/ovarian cancer family. One of these, a missense mutation, was also found in 2.8% of the general population, suggesting that this was not disease associated. Hamann et al. (1997) concluded that the low incidence of BRCA1 germline mutations in these families suggests the involvement of other susceptibility genes. Szabo and King (1997) collated information on the population genetics of BRCA1 and BRCA2 in populations from many countries of Europe as well as the U.S., Canada, and Japan. Tonin et al. (1998) noted that 4 mutations in BRCA1 and 4 mutations in BRCA2 had been identified in French-Canadian breast cancer and breast/ovarian cancer families from Quebec. To identify founder effects, they examined independently ascertained French-Canadian cancer families for the distribution of these 8 mutations. Mutations were found in 41 of 97 families. Six of 8 mutations were observed at least twice. The 4446C-T mutation (arg1443 to ter; 113705.0016) was the most common mutation found, followed by the BRCA2 8765delAG mutation (600185.0012). Together, these mutations were found in 28 of 41 families identified as having the mutation. The odds of detection of any of the 4 BRCA1 mutations was 18.7 times greater if one or more cases of ovarian cancer were also present in the family. The odds of detection of any of the 4 BRCA2 mutations was 5.3 times greater if there were at least 5 cases of breast cancer in the family. Interestingly, the presence of a breast cancer case less than 36 years of age was strongly predictive of the presence of any of the 8 mutations screened. Carriers of the same mutation, from different families, shared similar haplotypes, indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population. The identification of common BRCA1 and BRCA2 mutations could facilitate carrier detection in French-Canadian breast cancer and breast/ovarian cancer families. Gorski et al. (2000) studied 66 Polish families in each of which at least 3 related females had breast or ovarian cancer and at least 1 of these 3 had been diagnosed with cancer before the age of 50 years. A total of 26 families had both breast and ovarian cancers, 4 had ovarian cancers only, and 36 families had breast cancers only. Using SSCP followed by direct sequencing of observed variants, they screened the entire coding region of BRCA1 and BRCA2 for germline mutations. Mutations were found in 35 (53%) of the 66 families. All but one of the mutations were detected within the BRCA1 gene. BRCA1 abnormalities were identified in all 4 families with ovarian cancer only, and 67% of 27 families with both breast and ovarian cancer, and in 34% of 35 families with breast cancer only. The single family with a BRCA2 mutation had the breast-ovarian cancer syndrome. Seven distinct mutations were identified; 5 of these occurred in 2 or more families. In total, recurrent mutations were found in 33 (94%) of the 35 families with detected mutations. Gorski et al. (2000) found that 3 BRCA1 abnormalities, 5382insC, cys61 to gly (113705.0002), and 4153delA, accounted for 51%, 20%, and 11% of the identified mutations, respectively. De Los Rios et al. (2001) reported findings in Canadian families suggesting that most of the mutation-carrying families of Polish ancestry have the BRCA1 5382insC mutation. Sarantaus et al. (2001) studied 233 unselected Finnish ovarian carcinoma patients treated at the Helsinki University Central Hospital during the years 1989 to 1998. The patients were screened for 12 BRCA1 and 8 BRCA2 mutations identified previously in the Finnish population. Germline mutations of BRCA1/BRCA2 were detected in 13 of the patients (11 in BRCA1 and 2 in BRCA2) and 7 recurrent founder mutations accounted for 12 of the 13 mutations detected. All mutation-positive patients but one had serous or poorly differentiated carcinoma. The presence of breast and ovarian cancer in the same woman and/or early onset (under 50 years of age) breast cancer was characteristic of the majority (77%) of the mutation carriers. The population of Pakistan has been reported to have the highest rate of breast cancer of any Asian population (excluding Jews in Israel) and one of the highest rates of ovarian cancer worldwide. To explore the contribution of genetic factors to these high rates, Liede et al. (2002) conducted a case-control study of 341 case subjects with breast cancer, 120 case subjects with ovarian cancer, and 200 female control subjects from 2 major cities of Pakistan (Karachi and Lahore). The prevalence of BRCA1 or BRCA2 mutations among case subjects with breast cancer was 6.7%, and that among case subjects with ovarian cancer was 15.8%. Mutations of the BRCA1 gene accounted for 84% of the mutations among case subjects with ovarian cancer and 65% of mutations among case subjects with breast cancer. Most of the detected mutations were unique to Pakistan. Five BRCA1 mutations and 1 BRCA2 mutation were found in multiple case subjects and may represent candidate founder mutations. The penetrance of deleterious mutations in BRCA1 and BRCA2 was comparable to that of Western populations. The cumulative risk of cancer to age 85 years in female first-degree relatives of BRCA1 mutation-positive case subjects was 48%, and it was 37% for first-degree relatives of the BRCA2 mutation-positive case subjects. A higher proportion of case subjects with breast cancer than of control subjects were the progeny of first-cousin marriages (odds ratio = 2.1). The effects of consanguinity were significant for case subjects with early-onset breast cancer (age less than 40 years) (odds ratio = 2.7) and case subjects with ovarian cancer (odds ratio = 2.4). These results suggested that recessively inherited genes may contribute to breast and ovarian cancer risk in Pakistan. Diez et al. (2003) screened index cases from 410 Spanish breast/ovarian cancer families and 214 patients (19 of them males) with breast cancer for germline mutations in the BRCA1 and BRCA2 genes. They identified 60 mutations in BRCA1 and 53 in BRCA2. Of the 53 distinct mutations observed, 11 were novel and 12 had been reported only in Spanish families (41.5%); the prevalence of mutations in this set of families was 26.3%. The percentage was higher in families with breast and ovarian cancer (52.1%). Of the families with male breast cancer cases, 59.1% presented mutations in the BRCA2 gene. They found a higher frequency of ovarian cancer associated with mutations localized in the 5-prime end of the BRCA1 gene, but there was no association between the prevalence of this type of cancer and mutations situated in the OCCR of exon 11 of the BRCA2 gene. Five mutations accounted for 46.6% of BRCA1 detected mutations, whereas 4 mutations accounted for 56.6% of the BRCA2 mutations. The BRCA1 330A-G substitution (113705.0034) had a Galician origin (northwest Spain). Hartikainen et al. (2007) identified 5 different mutations in the BRCA1 or BRCA2 genes in 7 (19.4%) of 36 families with breast/ovarian cancer from eastern Finland. Hall et al. (2009) examined a comprehensive database of BRCA1/BRCA2 testing in the United States compiled over about 10 years (1996 to 2006). Full-sequence testing of the genes was performed in 46,276 women who met eligibility criteria. The largest ethnic subgroup was of Western or Central European ancestry (87.1%), followed by Latin American (4.2%), African (3.8%), Asian (2.6%), Native American (1.3%), and Middle Eastern (1.1%) ancestry. Individuals of Ashkenazi Jewish origin were excluded. Women of non-European descent were younger (mean age of 45.9 years) than European women (mean age of 50 years) at age of testing. Mutations were identified in 12.5% of women overall, but those of African and Latin American ancestries had significantly higher prevalences of deleterious BRCA1 and BRCA2 mutations (15.6% and 14.8%, respectively) compared with women of Western European ancestry (12.1%), primarily because of an increased prevalence of BRCA1 mutations in the former 2 groups. Overall, BRCA1 mutations were more common than BRCA2 mutations for every ethnicity except Asian, in which the frequency was equal (about 6.3% for each gene). The most common recurrent mutations per group were 5385insC (also known as 5382insC; 113705.0018) in BRCA1, accounting for 5.2% of all mutations among Western Europeans and 14.9% of all mutations among Central Europeans; 943ins10 (113705.0029) in BRCA1, accounting for 10% of all mutations among Africans; and 187delAG (also known as 185delAG; 113705.0003) in BRCA1, accounting for 6.7% of all mutations among Native Americans, 12.2% of all mutations among Latin Americans, and 15.2% of all mutations among Middle Eastern women.