NM_004456.4:c.1966G>A (p.Ala656Thr) is a missense variant in EZH2 that is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).¹ No additional pathogenic or benign criteria are met. The variant has not been reported in ClinVar, has no functional studies, no segregation data, no de novo observations, and in silico predictors are discordant (REVEL 0.753 damaging; BayesDel 0.311 benign).² With a single supporting criterion (PM2) and no conflicting benign evidence, the variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines (PMID:25741868).³