NM_006231.4:c.2778G>C (p.Glu926Asp) is a missense variant in exon 24 of POLE, located within the DNA polymerase domain (residues 393-1191). It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_Supporting).¹ The variant is not one of the established exonuclease-domain hotspot mutations (P286R, V411L, S297F, A456P, S459F) and does not appear in the León-Castillo et al. 2020 supplementary recurrence or in silico tables. It does not meet the custom POLE framework criteria for PM1, PS4, PP3, or BP4.² Computational predictions are equivocal: REVEL score of 0.281 is below pathogenic thresholds, BayesDel score of -0.171963 is benign-leaning, and SpliceAI predicts no splicing impact (max delta 0.01). Multiple lines of in silico evidence do not support a deleterious effect (PP3 not met) but also do not convincingly support a benign effect (BP4 not met).³ This variant has been reported in ClinVar as Uncertain significance (Variation ID 3225427) by a single clinical laboratory. No variant-specific functional studies, segregation data, or case-control evidence were identified.⁴ The only publication associated with this variant (PMID:25394175) is an ACMG/NSGC practice guideline on cancer predisposition referral indications that does not mention this specific variant and does not provide variant-level evidence (PP5 not met).⁵ With only PM2_Supporting met and no other pathogenic or benign criteria triggered, this variant remains a Variant of Uncertain Significance (VUS) under the León-Castillo 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules.⁶