Variation in BRCA1 cancer risks by mutation position.

Previous studies have reported variation in BRCA1 breast and ovarian cancer risks with mutation position, suggesting that mutations toward the 3' end of the gene are associated with lower ovarian cancer risks. We evaluated the evidence for genotype-phenotype correlations in 356 families with protein-truncating BRCA1 mutations. In contrast to previous reports, the ovarian:breast cancer ratio associated with mutations in a central region of the gene (nucleotides 2401-4190) was significantly higher than for other mutations [odds ratio, 1.70 (P = 0.017) compared with nucleotides 1-2400; odds ratio, 1.89 (P = 0.02) compared with nucleotides 4191-end]. The risks of breast and ovarian cancer conferred by mutations in different regions of the gene were estimated separately by conditional maximum likelihood. According to the best fitting model, the breast cancer risk associated with mutations in the central region was found to be significantly lower than for other mutations (relative risk, 0.71; 95% confidence interval, 0.58-0.86; P = 0.0002), whereas the ovarian cancer risk associated with mutations 3' to nucleotide 4191 was significantly reduced relative to the rest of the gene (relative risk, 0.81; 95% confidence interval, 0.66-1.00; P = 0.044). The cancer risks associated with missense mutations in the RING domain in exon 5 appear to be similar to those associated with protein-truncating mutations toward the 3' end of BRCA1, based on nine additional families.