Oncogenic Potential and Molecular Disruptions of ESR2 Coding and UTRs Variants: An Integrative In Silico Analysis

(1) Background: Estrogen Receptor Beta 1 (ERβ1), encoded by the ESR2 gene, plays a key tumor-suppressive role in hormone-dependent cancers. However, the impact of nonsynonymous single-nucleotide polymorphisms (nsSNPs) and untranslated region (UTR) variants in ESR2 remains underexplored.; (2) Methods: We performed a comprehensive in silico analysis of high-risk pathogenic nsSNPs and UTR variants using genomic data from Ensembl and predictive tools including PredictSNP, I-Mutant, MUpro, MutPred2, CScape, STRING, KEGG, GO, RegulomeDB, polymiRTS, and cBioPortal. Variants were assessed for their effects on ERβ1 protein structure, stability, regulatory interactions, and oncogenicity; (3) Results: Ninety-three missense nsSNPs were predicted as deleterious across all tools. Key variants such as C149G, D154G, and L380P destabilized ERβ1, especially within the DNA-binding and ligand-binding activation function 2 domains. Oncogenic drivers such as R198P and D154N showed high CScape scores and extremely low allele frequencies, indicating pathogenic potential. Mutations impaired coactivator recruitment and disrupted interactions with transcription factors including NCOA1, SP1, and JUN. Additionally, 3′ UTR variants such as rs4986938 and miRNA-disrupting SNPs such as rs139004885 demonstrated strong post-transcriptional regulatory effects; (4) Conclusions: This integrative computational study identifies high-impact ESR2 variants that compromise ERβ1 function and regulation, revealing their oncogenic potential in hormone-sensitive cancers. These findings highlight the importance of further experimental validation and their relevance in targeted therapy and biomarker development.