NM_006231.4:c.1708C>A (p.Leu570Met) is a missense variant in POLE, located at residue 570 outside the exonuclease domain in the polymerase domain. The variant is absent from gnomAD v2.1 (exomes) and v4.1 (exomes) population databases, meeting PM2 at moderate strength (PM2_Moderate).¹ Multiple in silico tools predict a benign impact: REVEL score 0.267 (benign-leaning, below the 0.5 pathogenic threshold), BayesDel score -0.221 (benign), and SpliceAI max delta 0.06 (no splice impact). This meets BP4 at supporting benign strength (BP4_Supporting).² The variant has been reported in ClinVar as Uncertain significance by 4 clinical laboratories (Variation ID 405767). It is not among the established POLE exonuclease-domain hotspot mutations identified by León-Castillo et al. 2020, and is absent from COSMIC and Cancer Hotspots.³ With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the net evidence is equivocal. The variant is classified as Variant of Uncertain Significance (VUS) under the León-Castillo et al. 2020 custom POLE framework and generic ACMG/AMP 2015 combination rules.⁴