LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-10
Case ID: NM_003620.3_c.1473dupT_20260710_022559
Framework: ACMG/AMP 2015
Variant classification summary

NM_003620.3:c.1473dupT

PPM1D  · NP_003611.1:p.(Asn492Ter)  · NM_003620.3
GRCh37: chr17:58740567 A>AT  ·  GRCh38: chr17:60663206 A>AT
Gene: PPM1D Transcript: NM_003620.3
Final call
Likely Pathogenic
PS3 strong PM1 moderate PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
PPM1D
Transcript
NM_003620.3
Protein
NP_003611.1:p.(Asn492Ter)
gnomAD AF
0.0 (v4.1)
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
This variant is absent from gnomAD v4.1 (0/1,614,190 alleles), satisfying PM2 at supporting level.
3
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).
4
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).
5
OncoKB classifies p.N492* as Likely Oncogenic with Likely Gain-of-function biological effect.
6
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.
7
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.
8
Overall classification: Likely Pathogenic based on PS3 (strong), PM1 (moderate), and PM2 (supporting) according to ACMG/AMP 2015 combination rules (1 strong + 1 moderate).
Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Not met While NM_003620.3:c.1473dupT (p.Asn492Ter) is a nonsense variant predicted to truncate the protein, truncating mutations in exon 6 of PPM1D are functionally characterized as gain-of-function, not loss-of-function. Multiple independent publications (PMID:23907125, PMID:24880341, PMID:25742468, PMID:29954749) demonstrate that C-terminal truncating mutations in PPM1D remove a degradation domain, resulting in a hyperstable protein with enhanced phosphatase activity that suppresses the DNA damage response. OncoKB classifies this variant as Likely Gain-of-function. Under ACMG/AMP 2015, PVS1 requires a loss-of-function disease mechanism and therefore does not apply to gain-of-function variants.
PMID:23907125 PMID:24880341 PMID:25742468 PMID:29954749 oncokb pvs1_gene_context pvs1_variant_assessment
PS1 N/A Not an SNV with a previously established pathogenic amino acid change at the same position.
PS2 Not met No de novo report for NM_003620.3:c.1473dupT was identified in any publication reviewed.
PS3 Met The variant p.Asn492Ter falls within the C-terminal degradation domain (amino acids ~400-605) of PPM1D that has been systematically characterized as a gain-of-function region by a CRISPR-Cas9 tiling screen (PMID:29954749, 265 gRNAs spanning the entire protein-coding region). This screen demonstrated that truncating mutations in amino acids 400-585 confer chemoresistance and selective advantage under DNA-damaging agents. Multiple independent publications confirm the gain-of-function mechanism: exon 6 truncating mutations produce a hyperstable protein with enhanced phosphatase activity that suppresses p53 and CHK2 phosphorylation (PMID:24880341, PMID:25742468, PMID:23907125). The variant is functionally characterized within a systematically tested range in >=2 independent publications.
PMID:29954749 PMID:24880341 PMID:25742468 PMID:23907125 oncokb
PS4 Not met No case-control study or significant enrichment data for NM_003620.3:c.1473dupT was identified in the reviewed literature.
PS5 N/A Not an SNV with a validated functional assay demonstrating a deleterious effect through an experimentally established functional study.
PM1 Met p.Asn492Ter truncates the protein within the well-characterized C-terminal degradation domain of PPM1D (exon 6, approximately amino acids 400-605). This domain is established as a critical regulatory region in multiple publications: its loss results in a hyperstable protein with enhanced phosphatase activity due to impaired proteasomal degradation (PMID:29954749, PMID:25742468, PMID:23907125). The truncation removes this functionally characterized degradation domain, consistent with the domain-level application of PM1.
PMID:29954749 PMID:25742468 PMID:23907125
PM2 Met NM_003620.3:c.1473dupT is absent from gnomAD v4.1 (0/1,614,190 alleles) and gnomAD v2.1. Under generic ACMG/AMP, allele frequency below 0.1% in population databases supports PM2 at supporting level.
gnomad_v4 gnomad_v2
PM3 N/A Skipped per instructions.
PM4 N/A Not an in-frame deletion/insertion or stop-loss variant.
PM5 N/A Unable to confirm classic same-residue PM5 semantics; this is a nonsense variant and no comparator missense at N492 was identified for PM5 evaluation.
PM6 N/A No de novo report for this variant identified; PM6 requires a confirmed de novo observation.
PP1 Not met No segregation data for NM_003620.3:c.1473dupT was identified in any reviewed publication.
PP2 N/A PP2 applies to missense variants in genes with low rate of benign missense variation and where missense is a common disease mechanism. PPM1D truncating mutations are the predominant pathogenic mechanism, not missense. Additionally, this is not a missense variant.
PP3 Not met SpliceAI predicts no significant splice impact (max delta score = 0.00). REVEL and BayesDel scores are not available for duplication variants. No in silico evidence supports a deleterious effect.
spliceai
PP4 Not met No specific phenotype or clinical data for the proband carrying NM_003620.3:c.1473dupT was available for review. PP4 requires the patient's phenotype or family history to be specific for a disease with a single genetic etiology.
PP5 Not met NM_003620.3:c.1473dupT is absent from ClinVar; no reputable source has classified this variant as pathogenic. PP5 requires a reputable source classification.
clinvar
BA1 Not met Variant is absent from gnomAD (0/1,614,190 alleles). BA1 requires allele frequency >1% in population databases.
gnomad_v4
BS1 Not met Variant is absent from gnomAD (0/1,614,190 alleles). BS1 requires allele frequency >0.3% in population databases under generic ACMG.
gnomad_v4
BS2 N/A No observation in healthy adults with full penetrance expected at early age identified. No homozygous or hemizygous data available.
BS3 Not met No benign functional studies for NM_003620.3:c.1473dupT were identified. All functional evidence in the reviewed literature demonstrates gain-of-function effects (enhanced phosphatase activity, chemoresistance), which are consistent with pathogenicity, not benign impact.
BS4 N/A No segregation data available to assess lack of segregation in affected family members.
BP1 N/A BP1 applies to missense variants in genes where a different molecular mechanism (truncation) is the primary cause of disease. This is a truncating variant, not a missense variant.
BP2 N/A No observation in trans with a pathogenic variant identified. No data available for BP2 evaluation.
BP3 Not met Not an in-frame deletion/insertion in a repetitive region without known function. BP3 does not apply to nonsense variants.
BP4 Not met SpliceAI max delta score = 0.00, indicating no predicted splice impact. However, the variant is a nonsense (p.Asn492Ter) with well-established functional consequences via gain-of-function mechanism. BP4 is directed at silent/synonymous and intronic variants without functional consequence, not at established functional variants.
spliceai
BP5 N/A Variant is absent from ClinVar; no reputable source classification as benign or likely benign exists.
clinvar
BP6 N/A Variant is absent from ClinVar; no reputable source has classified this variant as benign or likely benign.
clinvar
BP7 Not met Not a synonymous variant. BP7 does not apply to nonsense/frameshift variants.
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