BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and ovarian cancer.

The strongest risk factors currently known for inherited predisposition to breast and ovarian cancer are mutations in BRCA1 and BRCA2. Two mutations in BRCA1 and one mutation in BRCA2 have been identified that are present to a particularly high degree in the Ashkenazi Jewish population due to ancient founder effects. To clarify the role of ancient and novel BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population, families with a strong history of breast and ovarian cancer were examined. Seventeen Ashkenazi Jewish families with four or more breast or ovarian cancers were analyzed for ancient and novel mutations in BRCA1 and BRCA2. Ancient mutations existed in 9 families; 7 had the BRCA1 185 del AG mutation, 1 had BRCA1 5382 ins C, and 1 had BRCA2 6174 del T. A novel mutation, BRCA2 6425 del TT, was discovered in 1 of the remaining 8 families. Seven families with four or more cases of breast and ovarian cancer cannot be accounted for by either the ancient or novel mutations. Therefore, ancient mutations in BRCA1 and BRCA2 are present in approximately half of Ashkenazi Jewish families in this series, suggesting the possibility of novel mutations, either in BRCA1, BRCA2, or in currently unidentified gene(s), responsible for the remainder.