NM_000179.3(MSH6):c.1054G>A (p.Val352Ile) is a missense substitution in exon 4 of MSH6. This variant has been observed in gnomAD v4.1 at an overall allele frequency of 0.000093 (150/1,614,044 alleles, 1 homozygote), with a grpmax filtering allele frequency of 0.000199 (0.0199%). In gnomAD v2.1 the variant is present at an allele frequency of 0.000074 (21/282,596 alleles, 1 homozygote). It is absent from gnomAD-Canada v1.0.¹ The gnomAD v4.1 grpmax FAF (0.000199) is below the InSiGHT MSH6 VCEP BS1 threshold of ≥0.00022 and far below the BA1 threshold of ≥0.0022, so neither allele-frequency-based benign criterion is met. The overall allele frequency also exceeds the PM2 supporting threshold of <0.00002, so PM2 is not met.² Computational predictors strongly favor a benign effect: the HCI prior probability for pathogenicity is 0.0007 (far below the BP4_Supporting threshold of <0.11), SpliceAI predicts no splicing impact (max delta 0.00), REVEL score is 0.216, and BayesDel score is -0.443.³ The variant was detected as a somatic finding in a tumor from a suspected Lynch syndrome patient (PMID:25111426), where it was classified as class 2 (likely not pathogenic) with 34% variant allele frequency, retention of heterozygosity, and normal MMR protein expression by IHC. This somatic observation is consistent with a benign or low-impact variant but does not independently meet any VCEP criterion in a germline context.⁴ In ClinVar, this variant is reported as Likely benign by 9 clinical laboratories, Uncertain significance by 4, and Benign by 1 (ClinVar Variation ID: 182617). The InSiGHT expert panel has not issued a classification for this variant.⁵ No pathogenic or likely pathogenic missense variants at the same amino acid residue (Val352) were identified in InSiGHT VCEP records, so PM5 cannot be assessed.⁶ Applying the InSiGHT MSH6 VCEP version 2.0.0 combining rules: BP4_Supporting is the only criterion met. With a single benign supporting criterion, neither the Likely Benign threshold (≥2 benign supporting per Rule 19, or 1 benign strong + 1 benign supporting per Rule 18) nor any pathogenic threshold is reached. The variant is classified as Uncertain Significance.