NM_000179.3:c.836G>A (p.Ser279Asn) is a missense variant in MSH6 exon 4 that is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (allele frequency <0.00002).¹ Computational in silico predictors, including the MSH6-specific HCI prior probability of 0.0075, are consistent with a benign impact, meeting the VCEP BP4_Supporting criterion (HCI prior <0.11). SpliceAI predicts no splicing alteration (max delta score 0.00). REVEL score is 0.322 and BayesDel is -0.109.² No functional assay data, segregation data, de novo observations, tumor phenotype data, or same-residue pathogenic comparator variants are available for this variant. The variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories; ClinVar ID 234915) and has been observed once in somatic cancers (COSMIC COSV113286823).³ Per the MSH6 VCEP v2.0.0 combination rules: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point) are equivocal, resulting in a final classification of Uncertain Significance (VUS).⁴