NM_000179.2:c.440T>G (p.Leu147Arg) is a missense variant in exon 2 of MSH6. This variant is extremely rare in population databases, observed in 1 of 1,614,050 alleles in gnomAD v4.1 (AF = 6.20e-07), meeting PM2_Supporting under the InSiGHT MSH6 VCEP framework.¹ The variant is classified as Uncertain Significance in ClinVar by 3 clinical laboratories (ClinVar Variation ID: 1740396) with no expert panel submissions.² No variant-specific functional studies, cosegregation data, de novo observations, or tumor phenotype data were identified in the VCEP functional assay documentation, ClinVar submissions, or published literature.³ In silico predictors are inconclusive: HCI prior probability is 0.3529 (below PP3 thresholds), REVEL score is 0.222, BayesDel is -0.269843, and SpliceAI predicts no splicing impact (delta = 0.01). These do not meet thresholds for PP3 or BP4 under the VCEP framework.⁴ No same-residue pathogenic comparator variant (PM5) or same-amino-acid nucleotide change comparator (PS1) was identified in the VCEP pilot variants.⁵ With only PM2_Supporting met, and no benign or additional pathogenic criteria fulfilled, the variant is classified as Uncertain Significance under the InSiGHT MSH6 VCEP v2.0.0 combination rules.⁶