NM_000179.2:c.188C>T (p.Ser63Phe) is a missense variant in MSH6 exon 1. The variant is extremely rare, observed in 1 of 1,509,420 alleles (AF = 6.625e-07) in gnomAD v4.1 and absent from gnomAD v2.1, meeting PM2_Supporting under the InSiGHT MSH6 VCEP v2.0.0 framework.¹ Multiple in silico predictors are consistent with a benign effect. The HCI prior probability for p.Ser63Phe is 0.003, meeting BP4_Supporting (threshold < 0.11). REVEL score is 0.195, BayesDel score is -0.269, and SpliceAI predicts no splicing impact (max delta = 0.00).² PVS1 is not applicable (missense variant). PS1 is not met (no alternate nucleotide change encoding p.Ser63Phe classified as P/LP by this VCEP). PM5 is not met because PP3 is not supporting (HCI prior 0.003, far below PP3_Supporting threshold of >0.68). Multiple VCEP criteria are explicitly Not Applicable: PS4, PP5, PM1, PM6, PP2, BP1, BP2, BP6.³ The variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (VariationID: 1053294). It has been observed in somatic cancers (COSMIC COSV52275784, n = 6). No variant-specific functional data, segregation data, de novo occurrences, or tumor phenotype data were identified.⁴ At present, the only scored criteria are PM2_Supporting (pathogenic) and BP4_Supporting (benign), which offset. Multiple criteria remain unassessed due to absence of clinical, functional, and segregation data. Comprehensive assessment awaits functional assay results for p.Ser63Phe, tumor MSI/IHC data from variant carriers, and segregation analysis.