NM_014159.6:c.7572dup (p.Lys2525Ter) in SETD2 is a null variant in a gene for which loss of function is an established germline disease mechanism (SETD2 overgrowth syndrome), applied at PVS1_Moderate after downgrade for location in the last exon with predicted NMD escape and truncation of a non-critical C-terminal region.¹ This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, and absent from ClinVar, satisfying PM2_Moderate for a rare variant at extremely low population frequency.² No additional pathogenic, benign, or functional criteria are met. The three somatic-cancer publications reviewed (PMID:23417712, PMID:24509477, PMID:25728682) discuss SETD2 at the gene level but do not mention or characterize this specific variant. Overall classification: VUS (Variant of Uncertain Significance). Two moderate pathogenic criteria (PVS1_Moderate, PM2_Moderate) fall short of the Likely Pathogenic threshold under the ACMG/AMP 2015 combination rules, which require three moderate criteria or one strong plus one moderate for Likely Pathogenic. No benign criteria are met. The evidence is insufficient to classify this variant as either likely pathogenic or likely benign.³