NM_000249.3:c.1655C>T (p.Thr552Ile) is a missense variant in exon 14 of MLH1 that is extremely rare in population databases, observed in 2 of 1,612,688 alleles in gnomAD v4.1 (grpmax filtering AF = 3.65e-06), meeting PM2_Supporting under the InSiGHT MLH1 VCEP v2.0.0.¹ In silico predictors support a benign computational profile: the MLH1-specific HCI prior probability for pathogenicity is 0.0197, meeting BP4_Supporting (threshold <0.11). SpliceAI predicts no splicing impact (max delta = 0.01). REVEL (0.268) and BayesDel (0.361) are in the indeterminate range.² This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (ClinVar Variation ID: 1467499) with no expert panel classification. No publications were identified that specifically report this variant.³ No functional data, segregation data, tumor phenotype data, or de novo observations are available for this variant. Multiple criteria (PS3, PP1, PP4, PS2, BS3, BS4, BS2, BP5) could not be assessed due to absence of evidence. Under the InSiGHT MLH1 VCEP v2.0.0 combining rules, one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting) with no other criteria met results in classification as Uncertain Significance — conflicting or insufficient evidence to classify.⁴