NM_000249.4:c.1344G>T (p.Glu448Asp) is a missense variant in exon 12 of the MLH1 gene. It is extremely rare in population databases, with an allele frequency of 1.92e-05 in gnomAD v4.1 (31/1,614,034 alleles, 0 homozygotes), meeting PM2 at supporting strength.¹ Computational evidence strongly predicts a benign effect: the HCI prior probability for pathogenicity is 0.0024 (BP4_Supporting threshold <0.11 met), BayesDel score is -0.059 (benign range), and SpliceAI predicts no splicing impact (max delta = 0.03).² No functional data are available for this variant. It is not included in the VCEP calibrated functional assay documentation, and no publication reports variant-specific functional evidence for c.1344G>T.³ No segregation, de novo, or tumor pathology data are available for this variant. The variant has been reported in ClinVar as Uncertain Significance (VariationID 127612, 1-star review status) by 14 clinical laboratories, with one additional submission as Benign and one as Likely Benign.⁴ Applying the InSiGHT VCEP v2.0 combination rules: one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP4_Supporting) are met. No criteria at moderate, strong, or very strong strength are met in either direction. This yields a classification of Uncertain Significance.⁵