Of mice and (wo)men: genotype-phenotype correlations in BRCA1

Abstract

To date, over 6300 mutations in BRCA1, involving 1100 distinct sites, have been described and reported in the BIC (breast cancer information core) database. Since the first BRCA1 mutations in early-onset breast and ovarian cancer families were reported, several attempts to establish genotype-phenotype correlations for this gene have been reported. Moreover, in vitro data have suggested dominant-negative effects of putative mutant BRCA1 proteins over wild-type proteins. Genotype-phenotype correlations are not only important for predicting the clinical course of the disease and to allow tailor-made surveillance of individuals at risk, but also have implications for the elucidation of the molecular genetic mechanisms underlying BRCA1-mediated tumorigenesis and the development of gene transfer-based therapies. Here, we discuss genotype-phenotype correlations at the BRCA1 locus in mouse and man, and the functional aspects that may account for these observations.