BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Institut Curie Breast Cancer Group.

An account of familial aggregation in breast/ovarian cancer has become possible with the identification of BRCA1 germ-line mutations. We evaluated, for 249 individuals registered with the Institut Curie in Paris, the prior probability that an individual carried a mutation that predisposes to these diseases. We chose 160 women for BRCA1 analysis: 103 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 portion of the gene, by using denaturing gradient gel electrophoresis. Thirty-eight truncating mutations (32 frameshifts, 4 nonsense mutations, and 2 splice variants) were observed in 15% of women with a family history of breast cancer only and in 40% of those with a history of breast-ovarian cancer. Twelve of 25 distinct truncating mutations identified were novel and unique. Most BRCA1 mutations that had been reported more than five times in the Breast Cancer Information Core were present in our series. One mutation (5149del4) observed in two apparently unrelated families most likely originates from a common ancestor. The position of truncating mutations did not significantly affect the ratio of the risk of breast cancer to that of ovarian cancer. In addition, 15 DNA variants (14 missense mutations and 1 neutral mutation) were identified, 9 of which were novel. Indirect evidence suggests that seven of these mutations are deleterious.