The effects of novel point mutations in the BRCA1 protein structure of breast cancer patients with breast or ovarian familial cancer history: an in-silico study

Abstract

Pathogenic mutations in the BRCA1 gene are among the most significant genetic risk factors for breast cancer. Identifying these mutations is crucial for advancing prevention and treatment strategies. A substantial portion of genetic variants in BRCA1 remains unclassified due to limited functional evidence. Mutations in the Interesting New Gene (RING) and BRCA1 C-terminal (BRCT) domains are particularly associated with increased cancer risk. This study aims to identify and analyze novel mutations in these domains. Seven newly identified mutations—Q12H, K20D, and E84G in the RING domain, and Y1666D, T1675S, T1681A, and L1764Q in the BRCT domain—were evaluated using molecular dynamics simulations. The simulations revealed significant changes in the protein stability, flexibility, compactness, hydrogen bonding, and solvent-accessible surface area, with BRCT domain mutations showing more pronounced effects. This study represents the first comprehensive computational analysis to assess the structural and functional impact of these novel mutations and predict stabilization possibilities. By elucidating the conformational dynamics of BRCA1 mutations, our findings provide a foundation for experimental validation and the development of targeted therapeutic interventions.