NM_007194.4:c.1427C>T (p.Thr476Met) is a missense variant in CHEK2 exon 13, located within the protein kinase domain. This variant is present in gnomAD v2.1 at an allele frequency of 0.0313% (83/265,178 alleles, 0 homozygotes) and in gnomAD v4.1 at 0.0404% (644/1,595,894 alleles) including one homozygous carrier in the Middle Eastern subpopulation (AF 0.407%).¹ The variant is reported in ClinVar with conflicting classifications: Uncertain significance (29 clinical laboratories), Likely pathogenic (22 laboratories), and single submissions of Pathogenic, Likely benign, Likely risk allele, and Established risk allele (ClinVar Variation ID: 128060).² The Middle Eastern subpopulation allele frequency of 0.407% in gnomAD v4.1 exceeds the BS1 threshold of 0.3%, which is higher than expected for a pathogenic CHEK2 variant (BS1_Supporting).³ Multiple in silico tools predict a benign effect: BayesDel score 0.096 is in the benign range and SpliceAI max delta 0.03 predicts no splicing alteration. REVEL score 0.445 is borderline (BP4_Supporting).⁴ The variant was identified as a novel missense substitution in a Bulgarian breast cancer cohort (PMID:22862163, Angelova et al. 2012, n=145 patients), but no case-control statistics or functional characterization were provided. No well-established functional assay data, segregation studies, or case-control analyses are available to confirm or refute pathogenicity for this specific variant. The presence of a homozygous carrier in gnomAD v4.1 is notable for an autosomal dominant cancer predisposition gene, though formal BS2 criteria are not met because CHEK2-related cancer risk has incomplete penetrance and adult onset, and the phenotype of the homozygous individual is unknown.⁵ Overall, the available evidence includes one supporting benign criterion (BS1) and one supporting benign criterion (BP4), with no pathogenic criteria met. The evidence favors a benign interpretation but remains insufficient for a definitive classification.