NM_000249.4:c.2041G>A (p.Ala681Thr) is a missense variant in exon 18 of MLH1. This variant is extremely rare in population databases, with 3 alleles observed in 1,614,098 individuals in gnomAD v4.1 (AF=1.86e-06; grpmax FAF=2.8e-07), meeting PM2_Supporting per VCEP threshold.¹ Computational prediction using the MLH1-specific HCI prior yields a pathogenicity probability of 0.0273, meeting BP4_Supporting (<0.11) per VCEP specifications.² SpliceAI predicts no splicing impact (max delta score = 0.01).³ ClinVar reports this variant as Pathogenic, reviewed by the InSiGHT expert panel, with 17 clinical laboratories classifying as Pathogenic and 3 as Likely pathogenic.⁴ The VCEP functional assay spreadsheet does not include this variant; calibrated functional odds for pathogenicity are not available for PS3 adjudication.⁵ Two other missense variants at residue A681, c.2041G>C (p.Ala681Pro) and c.2042C>T (p.Ala681Val), are classified as Uncertain significance by the InSiGHT VCEP pilot, so PM5 cannot be applied.⁶ Under the VCEP combination rules, 1 pathogenic supporting criterion (PM2_Supporting) plus 1 benign supporting criterion (BP4_Supporting) yields Uncertain Significance — Conflicting Evidence (Rule31). However, the InSiGHT expert panel has classified this variant as Pathogenic in ClinVar, indicating that additional evidence (functional, segregation, and/or tumor data) not independently verifiable in this assessment was available to the panel.⁷