GERMLINE MUTATIONS OF THE BRCA1 GENE IN BREAST AND OVARIAN-CANCER FAMILIES PROVIDE EVIDENCE FOR A GENOTYPE-PHENOTYPE CORRELATION

Mutations in the BRCA1 gene, discovered in 1994, are associated with a n 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significan t correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our d ata suggest a transition in risk such that mutations in the 3' third o f the gene are associated with a lower proportion of ovarian cancer. H aplotype analysis supports previous data which suggest some BRCA1 muta tion carriers have common ancestors; however, we have found at least t wo examples where recurrent mutations appear to have arisen independen tly.