Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer

The lifetime risk of breast cancer may approach 80–90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2 (refs. 1–3). A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population 4–6 . We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, were heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age ( P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation of BRCA2 together may account for over a quarter of all early-onset breast cancer cases and two thirds of early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women.