NM_000179.3:c.1822A>G (p.Ile608Val) is a missense variant in exon 4 of MSH6. Only one criterion is met: BP4_supporting based on an HCI prior probability of 0.0038 (<0.11), with concordant in silico predictions (REVEL 0.185, BayesDel -0.360, SpliceAI Δ=0.01). All other applicable criteria are not met, and no pathogenic criteria are met.¹ This variant has been observed in gnomAD v4.1 at a grpmax FAF of 6.393e-05 (100/1,614,126 alleles, 0 homozygotes), which is above the VCEP PM2_supporting threshold of 0.00002 but below the benign BA1 (0.0022) and BS1 (0.00022) thresholds. The variant is present at low frequency in population databases, consistent with a rare variant of uncertain significance.² This variant has been reported in ClinVar as Uncertain significance by 10 of 11 clinical submitters and as Likely benign by 1 submitter (ClinVar Variation ID: 182626). No expert panel classification exists, and the review status is 'criteria provided, single submitter.' The variant has not been reported in COSMIC.³ No functional assay data are available for this variant in the InSiGHT MMR calibrated functional assay documentation. The variant was predicted to have 'no impact on MSH6' by the CoDP in silico tool (score 0.033; PMID:23621914), but this is computational prediction, not experimental functional evidence.⁴ Overall, NM_000179.3:c.1822A>G (p.Ile608Val) is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MSH6 VCEP v2.0 framework. Only BP4_supporting is met; all other applicable criteria are not met. No pathogenic criteria are met, and no benign criteria beyond BP4_supporting apply.⁵