Evaluation of: Konishi H, Mohseni M, Tamaki Aet al.Mutation of a single allele of the cancer susceptibility geneBRCA1leads to genomic instability in human breast epithelial cells.Proc. Natl Acad. Sci. USA108(43), 17773–17778 (2011). In their study, Konishi et al. generate and study cell lines that carry one mutant and one normal copy of BRCA1. These heterozygous (noncancerous) cells are noteworthy in that they carry an increased number of copy number alterations and have diminished DNA repair capacity. These observations go beyond the classical two-hit hypothesis for inherited cancers, whereby the cell phenotype is normal until the second allele is lost through somatic mutation or epigenetic silencing. They propose that BRCA1 heterozygosity is associated with increased genomic instability, which accelerates the mutation rate of other critical genes, including the second copy of BRCA1. They conclude that BRCA1 is a haploinsufficient tumor suppressor gene, which when lost through inheritance, increases a cell’s susceptibility to acquire further mutations.