NM_022552.4:c.1256del (p.Pro419LeufsTer232) is a frameshift deletion in exon 10 of DNMT3A, predicted to cause nonsense-mediated decay and complete loss of protein function. DNMT3A loss of function is an established mechanism for Tatton-Brown-Rahman syndrome (DNMT3A overgrowth syndrome), a germline disorder characterized by overgrowth, intellectual disability, and facial dysmorphism.¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting rarity in the general population.² No variant-specific functional studies, de novo reports, case-control data, or segregation analyses were identified in the reviewed literature for this specific variant. A single ClinVar submission from a clinical laboratory classifies the variant as Likely pathogenic for Tatton-Brown-Rahman overgrowth syndrome, but the evidence trail is limited to guideline citations without variant-specific published data.³ Under generic ACMG/AMP 2015 criteria, the combination of PVS1 (very_strong) and PM2 (supporting) is insufficient to reach a Likely Pathogenic classification, which requires at minimum 1 Very Strong + 1 Moderate or 1 Strong + 1-2 Moderate or 2 Moderate + 2 Supporting criteria. The classification falls into Variant of Uncertain Significance (VUS), favoring pathogenic, pending additional clinical or functional evidence.⁴