The rs2227943 (Leu929Ser) single nucleotide polymorphism is a suitable target for disrupting BRCA2

Abstract

The functional and structural impacts of the BRCA2 single nucleotide polymorphism rs2227943 (Leu929Ser) remain largely uncharacterized through detailed computational approaches, leaving a critical gap in our understanding of how this variant alters protein behavior. To address this disparity, this study investigates the structural impact of the BRCA2 single nucleotide polymorphism rs2227943 (Leu929Ser) as a potential susceptibility biomarker. Using strong in silico homology modeling and structural analysis via SWISS-MODEL and PyMOL, the constructed three- dimensional models of both the wild-type and mutant BRCA2 domains. These models were thoroughly validated for stereochemical reliability using PROCHECK, ERRAT and Verify3D. Although global superimposition of the native and mutant structures indicated a largely conserved backbone scaffold with a low Root Mean Square Deviation (RMSD) of 0.103 Å, local microenvironment analysis revealed significant perturbations (mutation analysis score: 13.74). Specifically, replacing a bulky, hydrophobic leucine with a polar serine at residue 929 forces a reorganization of side-chain orientations and disrupts essential intra-molecular hydrogen bonding and electrostatic networks. Because BRCA2 relies on precise conformational stability to facilitate DNA double-strand break repair, these localised structural shifts likely impair its essential protein-protein interactions. In conclusion, this computational analysis establishes the Leu929Ser variant as a highly disruptive mutation that compromises BRCA2 function, offering a promising candidate biomarker to enhance early risk prediction and tailor personalized oncological care globally.