Missense mutations in the BRCT domain of BRCA-1 from high-risk women frequently perturb strongly hydrophobic amino acids conserved among mammals.

Inherited missense mutations in the tumor suppressor gene, BRCA-1, may predispose to breast or ovarian cancer, but the exact effects on the protein are generally unknown. The COOH-terminal region of BRCA-1 encodes two BRCT repeats, which are partially conserved in mammalian species (human, dog, rat, and mouse; 60% amino acid identity). A bioinformatic analysis was conducted to evaluate 246 BRCT missense mutations from high-risk breast and/or ovarian cancer patients (reported in the NIH Breast Cancer Information Core database). It was hypothesized that amino acids conserved in evolution would be disproportionately targeted by the mutations and that conserved amino acids with strongly hydrophobic side chains would be disproportionately perturbed. A statistical model was developed, and chi(2) tests were used to determine whether missense mutations are randomly distributed throughout the BRCT repeats or whether they disproportionately target certain amino acids. The results showed that missense mutations disproportionately target amino acids that are identical in all four mammals (chi(2) = 46.01, P < 0.001). In addition, missense mutations disproportionately perturb conserved amino acids with strongly hydrophobic side chains (chi(2) = 68.57, P < 0.001) and alter the strongly hydrophobic property. The two most frequently observed known cancer-predisposing missense mutations in the BRCT repeats, M1775R and A1708E, conform to this pattern. These results suggest that missense mutations affecting highly conserved amino acids with strongly hydrophobic side chains can disturb important features of the BRCA-1 protein and may play a role in breast and ovarian cancer formation.