Variant classification summary

NM_003620.3:c.1535del

PPM1D · NP_003611.1:p.(Asn512IlefsTer2) · NM_003620.3

GRCh37: chr17:58740623 CA>C · GRCh38: chr17:60663262 CA>C

Gene: PPM1D Transcript: NM_003620.3

Final call

Likely Pathogenic

PVS1 supporting PM1 moderate PM2 supporting PM6 supporting PP5 supporting

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.(Asn512IlefsTer2)

gnomAD AF

5.576719550491619e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_003620.3:c.1535del (p.Asn512IlefsTer2) is a frameshift deletion in exon 6 of PPM1D, the terminal exon encoding the C-terminal regulatory domain.

2

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0012% (3/250,998), gnomAD v4.1 AF=0.00056% (9/1,613,852), and absent from gnomAD-Canada (PM2_Supporting).

3

The variant truncates the well-characterized C-terminal domain of PPM1D containing a proteasomal degradation signal. Multiple independent studies demonstrate that C-terminal PPM1D truncations result in a gain-of-function protein with increased stability and enhanced phosphatase activity, leading to suppression of the p53-mediated DNA damage response (PM1_Moderate).

4

The variant is a predicted loss-of-function frameshift; however, it occurs in the last exon and escapes nonsense-mediated decay. C-terminal PPM1D truncations produce gain-of-function rather than loss-of-function, warranting downgrade to PVS1_Supporting.

5

One clinical laboratory (Undiagnosed Diseases Network, NIH) reports this variant as de novo in a clinical testing context. While maternity and paternity are not confirmed, this constitutes an assumed de novo observation (PM6_Supporting).

6

This variant has been reported as Pathogenic in ClinVar by 4 independent clinical laboratories (Variation ID: 817626). The review status is 'criteria provided, single submitter' (PP5_Supporting).

7

No variant-specific functional data exists in the literature for c.1535del. The available studies characterize the general functional consequence of C-terminal PPM1D truncations as gain-of-function, supporting the domain-level PM1 assignment but not meeting PS3's requirement for variant-specific experimental evidence.

8

No in silico evidence supports pathogenicity; REVEL and BayesDel are not available for non-SNV variants, and SpliceAI predicts no splice impact (max delta=0.00).

9

This variant has been observed 33 times in somatic cancers (COSMIC: COSV59954107), consistent with a role in oncogenesis.

10

Overall classification: PVS1_Supporting + PM1_Moderate + PM2_Supporting + PM6_Supporting + PP5_Supporting = 1 Moderate + 4 Supporting criteria, which meets the threshold for Likely Pathogenic under generic ACMG/AMP 2015 combination rules.

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	Met	This frameshift variant in exon 6 (last exon) is a predicted loss-of-function variant in a gene where germline LoF is supported as a disease mechanism. However, the variant occurs in the terminal exon and therefore escapes nonsense-mediated decay. Multiple independent studies demonstrate that C-terminal truncating mutations in PPM1D exon 6 produce a gain-of-function protein with increased stability and enhanced phosphatase activity due to loss of a C-terminal degradation domain. Downgraded to PVS1_Supporting because the truncated protein retains functional phosphatase activity and the disease mechanism is gain-of-function rather than haploinsufficiency.	pvs1_gene_context pvs1_variant_assessment PMID:23907125 PMID:24880341 PMID:25742468 PMID:29954749
PS1	N/A	PS1 applies to same amino acid change via different nucleotide change. Not applicable to frameshift variants.
PS2	Not met	One ClinVar submission (SCV001499843, Undiagnosed Diseases Network, NIH) reported de novo origin, but no peer-reviewed publication with confirmed maternity and paternity is available. Does not meet PS2 threshold, which requires confirmed parentage.	clinvar
PS3	Not met	No variant-specific functional data exists for c.1535del (p.Asn512IlefsTer2). The literature characterizes the functional consequence of C-terminal PPM1D truncations generally (gain-of-function, increased stability, chemoresistance) but no study directly tested this exact variant or a systematically characterized range that includes position 512. Domain-level inference from studies testing other residues does not satisfy PS3's requirement for variant-specific or systematically-ranged functional evidence.	PMID:23907125 PMID:24880341 PMID:25742468 PMID:29954749
PS4	Not met	No case-control data or statistical enrichment analysis is available comparing variant frequency in affected individuals versus controls. The variant is reported in ClinVar as Pathogenic, but no published studies provide prevalence data in affected cohorts.	clinvar
PS5	N/A	PS5 applies to a different nucleotide change resulting in the same missense amino acid change as a known pathogenic variant. This is a frameshift variant.
PM1	Met	This variant truncates the well-characterized C-terminal regulatory domain of PPM1D (amino acids ~400-605, encoded by exon 6). The C-terminal domain contains a proteasomal degradation signal; truncating mutations that remove this domain result in stabilized, gain-of-function protein with enhanced phosphatase activity. Multiple independent publications (PMID:23907125, PMID:24880341, PMID:25742468, PMID:29954749) establish that the exon 6-encoded C-terminal domain is critical for PPM1D protein regulation through proteasomal degradation. The variant at position 512 produces a stop after 2 amino acids, removing the C-terminal 94 amino acids including the degradation domain.	PMID:23907125 PMID:24880341 PMID:25742468 PMID:29954749
PM2	Met	This variant is absent or present at extremely low frequency in population databases. gnomAD v2.1: 3/250,998 alleles (AF=0.0012%); gnomAD v4.1: 9/1,613,852 alleles (AF=0.00056%); gnomAD-Canada: absent. Maximum subpopulation AF is 0.00327% (South Asian, v2.1). All frequencies are well below the 0.1% PM2 threshold. Grpmax FAF is 2.93e-06 (v2.1).	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This is a frameshift deletion, not an in-frame change.
PM5	N/A	PM5 applies to a novel missense change at a residue where a different pathogenic missense change has been observed. This is a frameshift variant; the PM5 candidate framework confirmed inability to parse missense residue context from the normalized protein consequence.	pm5_candidates
PM6	Met	One ClinVar submission (SCV001499843) from the Undiagnosed Diseases Network, NIH, reports this variant as de novo in a clinical testing context. This constitutes an assumed de novo observation without published confirmation of maternity and paternity, meeting PM6 at supporting strength. No published case report with detailed phenotype information is available.	clinvar
PP1	Not met	No cosegregation data with disease in multiple affected family members is available.
PP2	N/A	PP2 applies to missense variants in genes with low rate of benign missense variation. This is a frameshift variant.
PP3	Not met	No computational evidence supports a deleterious effect. REVEL and BayesDel scores are not available for non-SNV variants. SpliceAI predicts no splice impact (max delta=0.00). HCI prior is not available for PPM1D.	spliceai
PP4	Not met	No patient phenotype or family history information is available in any of the reviewed sources to assess phenotypic specificity.
PP5	Met	This variant has been reported as Pathogenic in ClinVar by 4 independent clinical laboratories (ClinVar Variation ID: 817626). The review status is 'criteria provided, single submitter', a reputable source under generic ACMG guidelines. However, the underlying evidence used by these laboratories is not publicly available for independent evaluation, limiting PP5 to supporting strength.	clinvar
BA1	Not met	Maximum allele frequency in any population is 0.00327% (South Asian, gnomAD v2.1), far below the 1% BA1 threshold. This variant is not a common polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	Maximum allele frequency in any population is 0.00327% (South Asian, gnomAD v2.1), well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data available on observation of this variant in healthy adults where full penetrance would be expected at an early age.
BS3	Not met	Functional studies in the literature demonstrate that C-terminal PPM1D truncations are gain-of-function, conferring increased protein stability, enhanced phosphatase activity, and chemoresistance. This is not a benign effect; gain-of-function in a tumor suppressor pathway regulator is consistent with a pathogenic mechanism. BS3 requires well-established studies showing no damaging effect on protein function or splicing, which is contradicted by the available evidence.	PMID:23907125 PMID:24880341 PMID:25742468 PMID:29954749
BS4	Not met	No segregation data in affected family members is available to assess lack of segregation.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is itself a truncating variant.
BP2	Not met	No data available on observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a frameshift deletion.
BP4	Not met	No multiple lines of computational evidence suggest no impact. SpliceAI shows no splice effect (delta=0.00), but REVEL, BayesDel, and HCI prior are not available for this non-SNV variant. A single line of in silico evidence (SpliceAI only) is insufficient to meet BP4.	spliceai
BP5	Not met	No data available indicating this variant was found in a case with an established alternate molecular basis for disease.
BP6	Not met	ClinVar reports this variant as Pathogenic, not benign. BP6 requires a reputable source to report the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion.

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