BRCA1 SEQUENCE VARIATIONS IN 160 INDIVIDUALS REFERRED TO A BREAST OVARIAN FAMILY CANCER CLINIC/

An account of familial aggregation in breast/ovarian cancer has become possible with the identification of BRCA1 germ-line mutations. We eva luated, for 249 individuals registered with the Institut Curie in Pari s, the prior probability that an individual carried a mutation that pr edisposes to these diseases. We chose 160 women for BRCA1 analysis: 10 3 with a family history of breast cancer and 57 with a family history of breast-ovarian cancer. To detect small mutations, we generated and analyzed 35 overlapping genomic PCR products that cover the coding por tion of the gene, by using denaturing gradient gel electrophoresis. Th irty-eight truncating mutations (32 frameshifts, 4 nonsense mutations, and 2 splice variants) were observed in 15% of women with a family hi story of breast cancer only and in 40% of those with a history of brea st-ovarian cancer. Twelve of 25 distinct truncating mutations identifi ed were novel and unique. Most BRCA1 mutations that had been reported more than five times in the Breast Cancer Information Core were presen t in our series. One mutation (5149del4) observed in two apparently un related families most likely originates from a common ancestor. The po sition of truncating mutations did not significantly affect the ratio of the risk of breast cancer to that of ovarian cancer. In addition, 1 5 DNA variants (14 missense mutations and 1 neutral mutation) were ide ntified, 9 of which were novel. Indirect evidence suggests that seven of these mutations are deleterious.