Analysis of BRCA1/BRCA2 genes’ contribution to breast cancer susceptibility in high risk Jewish Ashkenazi women

Background Three mutations in BRCA1 (185delAG 5382InsC) and BRCA2 (6174delT) can be detected in a substantial proportion of Jewish Ashkenazi breast/ovarian cancer families. Family-specific pathogenic mutations in both genes can be detected in up to 5% of high risk Ashkenazim. The contribution of major gene rearrangements and seemingly pathogenic missense mutations to inherited breast cancer predisposition has never been systematically evaluated in Ashkenazim. Material and methods High risk, Jewish Ashkenazi women, non-carriers of the predominant Jewish BRCA1/BRCA2 mutations, were genotyped for major gene rearrangements in BRCA1/BRCA2 using Multiplex ligation-dependent probe amplification (MLPA), and for the occurrence rate of 6 seemingly pathogenic missense mutations in BRCA1 (R866C, R331S, R841W, Y179C, C61G, M1008I) using a modified restriction enzyme assay. Results Overall, 105 Jewish Ashkenazi high risk women, participated in the study: 104 with breast cancer [age at diagnosis (mean ± SD) 51.05 ± 11.13 years], one was affected with ovarian cancer (61 years). Two were found to carry the M1008I mutation in BRCA1 and none harbored any of the other missense mutations. MLPA reveled four changes (amplifications of exons 5, 17, 19 and 21) in BRCA1 in five patients, and six patients exhibited 4 MLPA-detectable abnormalities in BRCA2 (amplifications in exons 1b, 2, and deletions in exons 11a and 25). None of these abnormalities could be confirmed using quantitative PCR (qPCR) analysis. Conclusions Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews.