NM_005933.3:c.2684A>G (p.Lys895Arg) is a missense variant in exon 3 of KMT2A, a gene associated with autosomal dominant Wiedemann-Steiner syndrome. This variant is extremely rare in large population databases, with an allele frequency of 0.00283% in gnomAD v2.1 (8/282,230 alleles) and 0.00415% in gnomAD v4.1 (67/1,614,060 alleles), with no homozygotes observed. It is absent from gnomAD-Canada (PM2_Supporting).¹ Multiple lines of computational evidence predict a benign effect: REVEL score 0.224 (benign range), BayesDel score -0.154507 (benign), and SpliceAI predicts no splicing impact with a maximum delta score of 0.02 (BP4_Supporting).² This variant has been reported in ClinVar (Variation ID 1335086) with conflicting classifications: Uncertain significance by Invitae and Likely benign by CeGaT Center for Human Genetics Tuebingen. Neither submission reaches a definitive pathogenic or benign classification.³ The only publication associated with ClinVar submissions (PMID 28492532, Sherloc classification framework) does not mention this specific variant; it was reviewed in full text and confirmed to be a methodology reference only.⁴ This variant has been reported in COSMIC (COSV63290798) in 4 somatic cancer samples, but this does not constitute germline disease evidence. Several potentially relevant publications were identified by exploratory literature search (de novo report, functional studies, cosegregation data, domain hotspot analysis) but none of the associated PMIDs are present in the case directory for verification; these criteria (PS2, PS3, PS4, PM1, PM6, PP1, BS3) remain not assessed pending full-text retrieval and verification. Applying the generic ACMG/AMP 2015 combination rules (PMID 25741868): the criteria met are PM2_Supporting (pathogenic) and BP4_Supporting (benign). These are conflicting at the supporting level and are insufficient to reach a likely pathogenic or likely benign classification. The variant is classified as a Variant of Uncertain Significance (VUS).⁵