NM_002392.5:c.1036G>A (p.Glu346Lys) is a missense variant in MDM2, a proto-oncogene encoding a ubiquitin ligase and p53 inhibitor amplified in diverse cancers but lacking a well-established germline disease spectrum.¹ The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).² Multiple in silico predictors are concordant in predicting a benign effect: REVEL 0.037, BayesDel -0.61515, and SpliceAI max delta 0.00 (BP4_Supporting).³ The variant is absent from ClinVar with no classifications, no functional studies, no case reports, and no segregation data available.⁴ Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. These cancel, resulting in a classification of Variant of Uncertain Significance (VUS).⁵