NM_000249.4:c.1094G>A (p.Ser365Asn) is a missense variant in exon 12 of MLH1, absent from gnomAD v4.1 and v2.1 (PM2_Supporting per VCEP v2.0.0).¹ In silico predictors strongly favor a benign effect: HCI prior probability is 0.0025 (BP4_Supporting per VCEP, threshold <0.11), REVEL score is 0.321, and BayesDel score is -0.220172.² SpliceAI predicts no splicing impact (max delta score 0.01), confirming the variant does not create a cryptic splice site.³ The InSiGHT Locus-Specific Database (Thompson et al. 2013, PMID:22949387) classifies this variant as Class 5 (Pathogenic) based on a multifactorial likelihood model incorporating yeast-based MMR functional defect data and co-segregation in multiple families, but the quantitative calibrated functional odds and segregation likelihood ratios required for VCEP PS3 and PP1 strength assignment were not available in the case materials.⁴ ClinVar reports this variant as Uncertain Significance (4 clinical laboratories, criteria provided single submitter, ClinVar ID 1790197).⁵ No tumor pathology data (MSI status, MMR IHC, BRAF V600E, MLH1 methylation) was available to assess PP4 or BP5. Several criteria designated as Not Applicable by the VCEP were not assessed: PVS1 (missense, not null), PS4, PM1, PM6, PP2, PP5, BP1, BP2, BP6, BP7.⁶