NM_006231.4:c.6816G>A is a synonymous variant (p.Glu2272=) in exon 49 of the DNA polymerase epsilon catalytic subunit gene POLE. This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 criterion at supporting strength.¹ SpliceAI predicts no splicing impact (max delta score 0.00) for this synonymous variant located deep within exon 49, satisfying BP7 at supporting benign strength.² This variant has been reported in ClinVar as Likely benign by two clinical laboratories (Variation ID 1146301, 1-star review status, criteria provided by a single submitter).³ The León-Castillo et al. 2020 custom POLE framework, which provides gene-specific rules for PM1, PS4, PP3, and BP4, applies exclusively to exonuclease-domain missense variants and does not address this synonymous variant at codon 2272, which lies outside the exonuclease domain (residues 268–471).⁴ The variant has been observed once in somatic cancers (COSMIC COSV57678650) but has not been identified as a recurrent somatic hotspot or as a germline disease-associated variant in the literature reviewed. Overall, the variant meets PM2 (supporting) and BP7 (supporting benign), with all other assessed criteria not met or not applicable. With one pathogenic supporting and one benign supporting criterion, the evidence is insufficient for classification as either likely pathogenic or likely benign, resulting in a Variant of Uncertain Significance (VUS).⁵