Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population

Abstract

Background: The frequency and characteristics of disease in individuals who concomitantly harbor pathogenic mutations in both BRCA1 and BRCA2 genes are not established.Materials and methods: Data were collected from the database of Clalit Health Services National Familial Cancer Consultation Service. Probands referred to this clinical service and their family members are routinely tested for the three Jewish founder mutations (BRCA1:185delAG, 5382insC, BRCA2:6174delT). In addition, carriers identified in a population-based cohort of all cases diagnosed with breast cancer in Israel in 1987-1988 allowed the estimation of the population frequency of this phenomenon.Results: In the clinic-based series of 1191 carriers of mutations in BRCA1 or BRCA2 belonging to 567 families, 22 males and females (1.85%) from 17 different families (3.0%) were found to harbor two different mutations. These included 18 individuals (1.51%) who concomitantly carried the 185delAG BRCA1 and the 6174delT BRCA2 mutations and four individuals (0.34%) who carried the 5382insC BRCA1 and the 6174delT mutations. All individuals were heterozygote carriers and none had a double mutation of both founder mutations in the BRCA1 gene itself. Seven of the 16 double carrier women (46.7%) had a personal history of breast carcinoma, diagnosed at a mean age of 44.6, compared with 372/926 (40.2%) carriers of a single mutation diagnosed with a mean age at diagnosis of 48.1 [odds ratio (OR) = 1.3, 95% confidence interval (CI) 0.4-4.0]. One case (6.7%) had a personal history of ovarian carcinoma diagnosed at the age of 53 compared with 55/926 (5.9%) of the women with single mutation (OR = 1.1, CI = 0.2-7.6). The frequency of double mutations in the population-based national breast cancer cohort was 2.2% of all carriers, and 0.3% of all breast cancer cases in the Ashkenazi population in the cohort. The mean age at diagnosis of breast cancer was younger in the carriers of two mutations.Conclusion: Double carriers of mutations in the BRCA genes are rare and seem to be carrying a similar probability of developing breast and ovarian cancers as carriers of single mutations.

Characteristics of double heterozygosity for BRCA1 and BRCA2 germline mutations in Korean breast cancer patients

“…The most frequent mutations in BRCA1 gene were 509C [ A and 5615_5625del11insA, each of them was found 11 times, respectively. In BRCA2 gene, 7708C [ T was most frequently identified, which [18,21]. But there has been few reports regarding the prevalence among non-Ashkenazi carriers.…”

“…Most studies dealing with double heterozygosity for BRCA1 and BRCA2 mutations have been come from western countries, including Ashkenazi Jewish population [17][18][19][20][21]. But there has been few reports regarding double heterozygosity for the genes in Asia.…”

Identification of Germline BRCA1 Mutations among Breast Cancer Families in Northeastern Iran

“…The cloning of two major BC susceptibility genes, BRCA1 and BRCA2, in 1994 and 1995 (Futreal et al, 1994;Miki et al, 1994;Wooster et al, 1994; and the subsequent development of commercial genetic testing has brought hereditary cancer genetics into the public eye. BRCA1 mutations are uniformly more frequent than BRCA2 mutations (Malone et al, 2006;Hall et al, 2009;Kurian et al, 2010) with some exceptions (Nelson-Moseke et al, 2004) and a number of studies have reported an extremely rare case of familial BC with deleterious germline mutations in both BRCA1 and BRCA2 genes (double heterozygosity) (Lavie et al, 2011;Nomizu et al, 2012). The major role of BRCA1 appears to be DNA repair including homologous recombination and nucleotide excision repair (Roy et al, 2012).…”

Two patients with germline mutations in both BRCA1 and BRCA2 discovered unintentionally: a case series and discussion of BRCA testing modalities

“…Ashkenazi Jewish descent is the most important predictor for compound heterozygosity [2][3][4][5][6][7][8][9]. The likelihood of being a carrier of a common BRCA1 or BRCA2 founder mutation is as high as 1 in 40, and it is estimated that 0.3% of all breast cancer cases in the Ashkenazi Jewish population are compound heterozygotes [10,11]. However, the prevalence of these mutations in a non-Ashkenazi population is as low as 0.11% for BRCA1 and 0.12% for BRCA2 [12].…”