<![CDATA[The BRCA1 gene plays a critical role in maintaining genomic stability through DNA damage repair; therefore, mutations in this gene may increase the risk of breast and ovarian cancers. Numerous novel variants identified through sequencing are classified as Variants of Uncertain Significance (VUS), referring to variants whose biological effects remain undetermined. This study evaluated the potential pathogenicity of three BRCA1 VUSs using an in silico approach based on comparative protein sequence analysis. Three variants—p.Tyr1863Cys, p.Ser1180Arg, and p.Thr37Pro—were selected to represent mutations located in the C-terminus, central region, and N-terminus (RING domain), respectively. Wild-type Homo sapiens and mammalian ortholog protein sequences were retrieved from UniProt and aligned using MEGA to assess residue conservation, complemented by phylogenetic analysis to provide an evolutionary context. BLASTp was employed to assess sequence similarity and the homologous relationship between human BRCA1 and its orthologs. The results revealed distinct patterns of residue conservation: p.Tyr1863Cys occurred at a residue with low conservation, p.Ser1180Arg at a highly conserved residue, and p.Thr37Pro at a completely conserved residue within the RING domain. Integration of evolutionary conservation, domain localization, and changes in the chemical properties of the substituted residues indicated that p.Thr37Pro had the highest potential pathogenicity, followed by p.Ser1180Arg and p.Tyr1863Cys. All findings are predictive and require further experimental validation.]]>
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