An identical novel mutation in BRCA1 and a common haplotype in familial ovarian cancer in non-Ashkenazi Jews

Unique germline mutations in BRCA1 and BRCA2 account for inherited predispo sition to breast and ovarian cancer in high-risk families. In Jewish high-r isk individuals of Ashkenazi (east European) descent, three predominant mut ations, 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations, and two of these mutation s (185delAG and 6174delT) are also found at about 1% each in the general Je wish-Ashkenazi population. We identified a novel BRCA1 mutation in two Jewi sh-non-Ashkenazi families with ovarian cancer: a thymidine to guanidine alt eration at position 3053, resulting in substitution of tyrosine at codon 10 17 for a stop codon (Tyr1017Ter). The mutation was first detected by protei n truncation test (PTT) and confirmed by sequencing and a modified restrict ion digest assay. Allelotyping of mutation carriers using intragenic BRCA1 markers revealed that the haplotype was identical in these seemingly unrela ted families. No mutation carrier was found among 118 unselected Jewish ind ividuals of Iranian origin. Our findings suggest that this novel mutation s hould be incorporated into the panel of mutations analysed in high-risk fam ilies of the appropriate ethnic background, and that the repertoire of BRCA 1 mutations in Jewish high-risk families may be limited, regardless of ethn ic origin.