NM_003620.3:c.1473dupT (p.Asn492Ter) is a nonsense variant in exon 6 of PPM1D that truncates the protein within the C-terminal degradation domain. This variant is absent from gnomAD v4.1 (0/1,614,190 alleles), satisfying PM2 at supporting level.¹ Functional evidence from a CRISPR-Cas9 tiling screen demonstrates that truncating mutations in the PPM1D exon 6 region (amino acids 400-585, encompassing N492) confer chemoresistance and selective advantage through a gain-of-function mechanism (PMID:29954749).² Multiple independent studies confirm that exon 6 truncating PPM1D mutations produce a hyperstable protein with enhanced phosphatase activity due to loss of the C-terminal degradation domain (PMID:24880341, PMID:25742468, PMID:23907125).³ OncoKB classifies p.N492* as Likely Oncogenic with Likely Gain-of-function biological effect.⁴ PVS1 is not met because truncating PPM1D exon 6 mutations are gain-of-function, not loss-of-function; the variant produces a hyperstable, hyperactive protein rather than a null allele.⁵ PM1 is met at moderate level: p.Asn492Ter removes the C-terminal degradation domain, a critical regulatory region whose loss is functionally characterized across multiple studies.⁶ Overall classification: Likely Pathogenic based on PS3 (strong), PM1 (moderate), and PM2 (supporting) according to ACMG/AMP 2015 combination rules (1 strong + 1 moderate).⁷