Abstract
Unique germline mutations in BRCA1 and BRCA2 account for inherited predisposition to breast and ovarian cancer in high-risk families. In Jewish high-risk individuals of Ashkenazi (east European) descent, three predominant mutations, 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations, and two of these mutations (185delAG and 6174delT) are also found at about 1% each in the general Jewish-Ashkenazi population. We identified a novel BRCA1 mutation in two Jewish-non-Ashkenazi families with ovarian cancer: a thymidine to guanidine alteration at position 3053, resulting in substitution of tyrosine at codon 1017 for a stop codon (Tyr1017Ter). The mutation was first detected by protein truncation test (PTT) and confirmed by sequencing and a modified restriction digest assay. Allelotyping of mutation carriers using intragenic BRCA1 markers revealed that the haplotype was identical in these seemingly unrelated families. No mutation carrier was found among 118 unselected Jewish individuals of Iranian origin. Our findings suggest that this novel mutation should be incorporated into the panel of mutations analysed in high-risk families of the appropriate ethnic background, and that the repertoire of BRCA1 mutations in Jewish high-risk families may be limited, regardless of ethnic origin.
Highlights
Germline mutations in BRCAJ and BRCA2 genes presumably account for the genetic predisposition and increased risk for breast and ovarian cancer in the majority of families with inherited predisposition to these cancers (Hall et al, 1990; Easton et al, 1993; Miki et al, 1994; Wooster et al, 1995)
More than 100 germline mutations have been identified within the BRCAJ gene (Castilla et al, 1994; Szabo and King, 1995; Langston et al, 1996), as well as several dozen in BRCA2, that, by and large, are unique to each high-risk family
In family A, of Jewish Persian origin, ovarian cancer in the index case was diagnosed at age 40 years
Summary
Germline mutations in BRCAJ and BRCA2 genes presumably account for the genetic predisposition and increased risk for breast and ovarian cancer in the majority of families with inherited predisposition to these cancers (Hall et al, 1990; Easton et al, 1993; Miki et al, 1994; Wooster et al, 1995). A notable exception are the Jewish high-risk individuals, in whom three predominant mutations, 185delAG and 5382insC (BRCAI) and 6174delT (BRCA2), seem to account for a substantial proportion of germline mutations (Abeliovich et al, 1997). Two of these predominant mutations, 185delAG and 6174delT, are found in the general Jewish-Ashkenazi population at a surprisingly high rate of approximately 1% each; the 5382insC mutation is found at slightly lower rates (Streuwing et al, 1995; O'ddoux et al, 1996).
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