Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families

Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 account for the majority of families with hereditary breast cancer. Among women with BRCA1 mutations, the lifetime risk of breast cancer exceeds 80%, and the risk of ovarian cancer approaches 50%. The risk for breast cancer in carriers of BRCA2 mutations is also high, but may vary with the position or type of mutation. Although the risk of ovarian cancer is lower for BRCA2 than for BRCA1 mutation carriers, several other cancers appear to be part of the BRCA2 spectrum, including male breast cancer and pancreatic cancer. Both genes are large: the coding region of BRCA1 contains 5,592 base pairs distributed over 22 exons and BRCA2 contains 10,254 base pairs of coding sequence within 27 exons. Because of the size of these genes, mutation detection is difficult by current techniques. The task of ruling out a mutation in both genes represents a considerable undertaking for the diagnostic laboratory - although this is what the patient or physician most often requests. Because of the similarity in the sites of cancer that are associated with the two genes, exclusion of a mutation in a single gene is of limited clinical value.