Thus, missense variants add modestly to the contribution of BRCA1 and BRCA2 variants to breast cancer incidence, but make a relatively more substantial contribution for ATM. The differences between genes in the relative contributions of missense variants to risk presumably reflect the relative proportion of residues within functional domains in which disrupted function is associated with cancer risk, and the size of those domains. The gene discussed is BRCA1; the disease is breast carcinoma.