NM_024408.3:c.7354C>T (p.Gln2452Ter) is a nonsense variant in the last exon of NOTCH2 that truncates the C-terminal portion of the PEST degradation domain.¹ The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at moderate strength.² The truncation removes part of the PEST domain, a well-characterized functional domain responsible for NOTCH2 protein degradation, meeting PM1 at moderate strength.³ PVS1 is not met because NOTCH2 PEST domain truncations are established as gain-of-function (Hajdu-Cheney syndrome), not loss-of-function, and the alteration predicts NMD escape.⁴ No variant-specific functional data, de novo reports, segregation data, or ClinVar classifications are available. Remaining criteria are not met or not applicable. Overall evidence: 2 moderate pathogenic criteria (PM1 + PM2) with no benign criteria. This combination does not reach the threshold for Likely Pathogenic under generic ACMG/AMP 2015 rules (requires 2 moderate + 2 supporting, or 3 moderate, or 1 strong + 1-2 moderate). The variant is classified as a Variant of Uncertain Significance (VUS).⁵