Familial breast cancer: double heterozygosity for BRCA1 and BRCA2 mutations with differing phenotypes

The co-existence of mutations in the BRCA1 and BRCA2 genes is unusual, and to date almost all cases reported have had at least one of the Ashkenazi founder mutations. We report on a family in whom individuals are double heterozygotes for a mutation in BRCA1 and a novel splice site mutation in BRCA2. The phenotypes are discordant, where one sister has had multiple cancers in the BRCA spectrum, while the other is unaffected at 65 years of age. The utility of testing is discussed, and the completion of diagnostic testing despite the finding of a potentially causal mutation is validated.