Variant classification summary

NM_003620.3:c.1384C>T

PPM1D · NP_003611.1:p.(Gln462Ter) · NM_003620.3

GRCh37: chr17:58740479 C>T · GRCh38: chr17:60663118 C>T

Gene: PPM1D Transcript: NM_003620.3

Final call

Likely Pathogenic

PVS1 strong PS3 supporting PM1 moderate PM2 supporting PP5 supporting

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.(Gln462Ter)

gnomAD AF

1.2390775315593048e-06 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_003620.3:c.1384C>T (p.Gln462Ter) is a nonsense variant introducing a premature termination codon in exon 6 of PPM1D, the terminal exon of the gene.

2

Loss of function is an established disease mechanism for PPM1D in the germline, and this null variant meets PVS1 at strong strength, downgraded from very strong due to location in the terminal exon where nonsense-mediated decay is predicted to be escaped per ClinGen SVI PVS1 recommendations (PMC6185798).

3

The variant is located in exon 6, the well-established mutation cluster region for PPM1D truncating mutations, meeting PM1 at moderate strength.

4

This variant is extremely rare in population databases, absent from gnomAD v2.1 and gnomAD-Canada, with an allele frequency of 0.00012% (2/1,614,104 alleles) in gnomAD v4.1, meeting PM2 at supporting strength.

5

Functional studies reported in the literature confirm that c.1384C>T (p.Q462X) is a gain-of-function mutation producing a hyperstable protein with enhanced phosphatase activity, meeting PS3 at supporting strength.

6

This variant has been reported as Likely pathogenic by two clinical laboratories in ClinVar, meeting PP5 at supporting strength.

7

Combined classification: 1 strong (PVS1) + 1 moderate (PM1) + 3 supporting (PM2, PS3, PP5) meets the threshold for Likely Pathogenic under the generic ACMG/AMP 2015 classification framework.

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	Null variant (nonsense) in PPM1D where loss of function is an established germline disease mechanism. The variant introduces a premature termination codon at position 462 in exon 6 (the terminal exon, 6/6), which is predicted to escape nonsense-mediated decay under the ClinGen SVI PVS1 decision framework (PMC6185798), warranting PVS1 at strong rather than very strong level.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No known pathogenic variant at the same nucleotide position (c.1384) with a different nucleotide change.
PS2	Not assessed	No de novo data available for this variant in any reviewed source.
PS3	Met	Functional assessment of c.1384C>T (p.Q462X) was reported as confirming gain-of-function in the literature (PMID:25742468, citing prior work by Ruark et al. 2013). The truncating mutation produces a hyperstable protein with enhanced phosphatase activity, consistent with the established gain-of-function mechanism for exon 6 PPM1D truncations.	PMID:25742468
PS4	Not assessed	No case-control studies comparing variant frequency in affected vs. unaffected populations are available for this specific variant.
PS5	N/A	PS5 is a deprecated criterion; use PM2 and PP5 for the relevant evidence instead.
PM1	Met	The variant is located in exon 6 of PPM1D, within the well-established mutation cluster region (codons ~400–550) where virtually all pathogenic truncating mutations in this gene are found. Multiple independent studies confirm exon 6 as a hotspot for gain-of-function truncating mutations in both somatic and germline contexts.	PMID:25742468 PMID:23907125 PMID:30304655 PMID:29954749
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD-Canada, and has an extremely low allele frequency in gnomAD v4.1 (AF=1.24e-6, 2/1,614,104 alleles, 0 homozygotes), well below the PM2 threshold of 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue. This variant is a nonsense change (Q462*), not a missense variant, and the automated PM5 candidate search found no comparable same-residue missense variants.	pm5_candidates
PM6	Not assessed	No de novo data available for this variant in any reviewed source.
PP1	Not assessed	No segregation data available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense variant.
PP3	N/A	PP3 applies to missense variants with multiple lines of computational evidence supporting a deleterious effect. This is a nonsense variant for which pathogenicity is mediated through protein truncation; the deleterious effect is already captured by PVS1. PP3 should not be stacked with PVS1 for the same variant.
PP4	Not assessed	No patient phenotype or family history data available for this variant to evaluate specificity of presentation.
PP5	Met	This variant has been reported as Likely pathogenic by two clinical laboratories in ClinVar (ClinVar variation ID: 1710039), with criteria provided. Although neither submission is from an expert panel, the concordant classification from multiple clinical testing laboratories supports pathogenicity.	clinvar
BA1	Not met	The variant has an allele frequency of 0.00012% in gnomAD v4.1, far below the BA1 threshold of 1%.	gnomad_v4
BS1	Not met	The variant has an allele frequency of 0.00012% in gnomAD v4.1, far below the BS1 threshold of 0.3%. It is absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data available on observation of this variant in healthy adults with full penetrance expected at an early age.
BS3	Not met	Available functional evidence indicates this is a gain-of-function variant (PMID:25742468), not a benign variant with no functional effect. BS3 is not met.	PMID:25742468
BS4	Not assessed	No segregation data available showing lack of cosegregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a nonsense (truncating) variant.
BP2	N/A	No evidence for an in trans pathogenic variant in a recessive disorder; not applicable in the absence of such data.
BP3	N/A	Skipped — in-frame deletion/insertion criteria not relevant to this substitution variant.
BP4	N/A	BP4 applies to missense variants with multiple lines of computational evidence suggesting no impact. This is a nonsense variant; the deleterious effect is captured by PVS1. BP4 should not be stacked with PVS1 for the same variant.
BP5	N/A	BP5 applies to variants found in a case with an alternate molecular basis for disease. No such data available and not relevant to this assessment.
BP6	Not met	BP6 requires a reputable source to report the variant as benign. ClinVar reports this variant as Likely pathogenic, not benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. This is a nonsense variant, not synonymous.

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