NM_006231.4:c.3959G>A (p.Arg1320Gln) in POLE is classified as a Variant of Uncertain Significance (VUS).¹ This variant is a missense substitution in exon 31 of 49, located in the C-terminal region of POLE, far outside the well-characterized exonuclease domain (residues ~268-471).² The variant is present at very low frequency in population databases: gnomAD v2.1 allele frequency 0.0032% (8/249,426 alleles) and v4.1 allele frequency 0.0016% (25/1,613,522 alleles), with no homozygotes observed (PM2_Supporting).³ Multiple in silico tools predict a benign effect: REVEL score 0.225, BayesDel score -0.2976, and SpliceAI max delta 0.02 (BP4_Supporting).⁴ The variant is not one of the five established pathogenic POLE exonuclease-domain hotspot mutations (P286R, V411L, S297F, A456P, S459F) and is absent from the recurrent variant list in the Leon-Castillo et al. 2020 endometrial carcinoma cohort analysis.⁵ ClinVar classifies this variant as Uncertain Significance with 5 clinical laboratory submissions and review status 'criteria provided, single submitter' (1-star). No expert panel review has been performed.⁶ No functional studies, segregation data, de novo observations, or case-control data are available for this variant. The reviewed literature (Karbassi et al. 2016, PMID:26467025; Hampel et al. 2015, PMID:25394175; Nykamp et al. 2017, PMID:28492532) consists of variant classification methodology papers that do not mention this variant.⁷ The net evidence balance is one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), resulting in a classification of Uncertain Significance under the ACMG/AMP 2015 framework.⁸