New nonsense mutation in the breast cancer‐1 gene in a French site‐specific breast cancer family

BRCA-1 is a tumor suppressor gene involved in ∼45% of breast cancer families (Miki et al., 1994) and 92% of breast-ovarian cancer families with no male breast cancer. We report a new nonsense mutation detected in a French breast-cancer family with three early-onset breast cancers but no ovarian cancers. By sequencing, a C to T substitution in codon 1604 (exon 16) was detected creating a stop codon (Gln1604ter). The BRCA-1 mutation was detected in an affected woman and her unaffected mother, > 80 years old. It strengthened the evidence of incomplete penetrance of BRCA-1 mutations, which is estimated to be nearly 85%. Remarkably, the nonsense mutation is not found in another sister with mammary dysplasia. Until now, 90 mutations of BRCA-1 have been described; 64% are frameshift and 18% are nonsense mutations, which truncate the protein product leaving no doubt about their deleterious effect in cancer hereditary predisposition. In exon 16, three other mutations have been detected: one missense mutation (Pro1637Leu) in an American ovarian cancer family (Futreal et al., 1994), one frameshift mutation at codon 1656, generating a stop codon in an American breast/ovarian cancer family (Castilla et al., 1994), and one nonsense mutation (Tyr1563fter) in a French breast/ovarian cancer family (Serova et al., 1996). The relationship between genotype and phenotype hints that mutations in the 3′ third of the gene are associated with lower incidence of ovarian cancer in affected families (Gayther et al., 1995). Interestingly, our mutation occurred in a site-specific breast cancer family corroborating this trend.