NM_003620.3:c.1525G>C

PPM1D · NP_003611.1:p.(Asp509His) · NM_003620.3

GRCh37: chr17:58740620 G>C · GRCh38: chr17:60663259 G>C

Gene: PPM1D Transcript: NM_003620.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.(Asp509His)

gnomAD AF

8.612261133670968e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_003620.3:c.1525G>C (p.Asp509His) is a missense variant in exon 6 of PPM1D that is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (AF = 0.0086%, 139/1,613,978 alleles, 0 homozygotes; grpmax FAF = 0.0096%), meeting PM2 at supporting level.

Multiple lines of in silico evidence suggest a benign effect: REVEL score 0.325 (benign range), BayesDel score 0.081 (tolerated), and SpliceAI max delta 0.00 (no predicted splice impact), meeting BP4 at supporting benign level.

This variant has been reported in ClinVar as Likely benign by a single clinical laboratory (Labcorp/Invitae, 1-star, criteria provided, single submitter). This does not reach the 3-star expert panel threshold for PP5 or BP6 application.

No variant-specific functional studies, segregation data, de novo observations, or case-control data were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.

The variant has not been reported in COSMIC and does not lie in a statistically significant mutational hotspot per cancerhotspots.org.

Using generic ACMG/AMP 2015 combination rules (PMID:25741868): PM2 (supporting) and BP4 (supporting benign) are opposing and cancel. No criteria combination threshold for pathogenic, likely pathogenic, benign, or likely benign is reached. This variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	NM_003620.3:c.1525G>C is a missense variant (p.Asp509His); it does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions.	pvs1_generic_framework
PS1	Not met	No prior observation of a pathogenic variant resulting in the same amino acid change (p.Asp509His or p.D509H) was identified in ClinVar, literature, or other curated databases.
PS2	Not met	No de novo observation with confirmed parentage was identified for this variant in the available literature or databases.
PS3	Not met	No variant-specific functional studies testing NM_003620.3:c.1525G>C (p.Asp509His) were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. COSMIC has no entry. The five supporting papers from PVS1 gene context describe other PPM1D variants (truncating mutations, c.1607G>A, c.1654C>T) but none tested or mentioned c.1525G>C.	oncokb
PS4	Not met	No case-control or cohort enrichment data comparing affected versus control populations was identified for this variant.
PS5	Not met	No alternative nucleotide change at c.1525 resulting in the same amino acid change (p.Asp509His) has been established as pathogenic.
PM1	Not met	Residue D509 is not a statistically significant mutational hotspot per cancerhotspots.org. While PPM1D exon 6 harbors truncating mutation hotspots in cancer, D509H is a missense change and there is no residue-specific hotspot or well-characterized functional domain defined at this position for missense substitutions.
PM2	Met	NM_003620.3:c.1525G>C is absent from gnomAD v2.1 and present at very low frequency in gnomAD v4.1 (overall AF = 0.0086%, 139/1,613,978 alleles, 0 homozygotes; grpmax FAF = 9.607e-05). This is well below the 0.1% PM2 threshold for a rare variant.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue (D509) alternative pathogenic missense variant was identified. PM5 candidate harvesting was unable to confirm classic same-residue comparators in ClinVar.
PM6	Not met	No de novo observation (with or without confirmed parentage) was identified for this variant.
PP1	Not met	No cosegregation data with disease in affected family members was identified for this variant.
PP2	Not met	HCI prior probability is not available for PPM1D. Without gene-level missense constraint data (e.g., Z-score), PP2 cannot be applied.
PP3	Not met	Multiple in silico tools predict a benign or tolerated effect: REVEL score 0.325 (below 0.5 threshold), BayesDel score 0.081 (well below damaging threshold), and SpliceAI max delta 0.00 (no predicted splice impact). Computational evidence does not support a damaging effect.	revel bayesdel spliceai
PP4	Not met	No phenotype or family history data specific to a PPM1D-associated disorder was available for the proband harboring this variant.
PP5	Not met	ClinVar reports this variant as Likely benign (1-star, criteria provided, single submitter). PP5 requires a 3-star expert panel classification of pathogenic; a single submitter classification as likely benign cannot be leveraged for PP5. The single submitter classification is not a reputable source reporting the variant as pathogenic.	clinvar
BA1	Not met	gnomAD v4.1 allele frequency is 0.0086%, well below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	gnomAD v4.1 allele frequency is 0.0086%, well below the 0.3% BS1 threshold for a rare variant being too common for a fully penetrant disorder.	gnomad_v4
BS2	Not met	No data available on observation of this variant in healthy adults at an age where full penetrance of a PPM1D-associated disorder would be expected.
BS3	Not met	No variant-specific functional studies demonstrating a benign effect for NM_003620.3:c.1525G>C were identified in the literature or curated databases.
BS4	Not met	No nonsegregation data (variant absent in affected family members) was available for this variant.
BP1	Not met	While PPM1D truncating variants are associated with cancer predisposition, missense variants in PPM1D have also been reported as potentially disease-associated (e.g., c.1607G>A, p.Arg536Lys in PMID:27401275). PPM1D is not a gene where only truncating variants cause disease; BP1 does not apply.
BP2	Not met	No observation of this variant in trans with a known pathogenic PPM1D variant was identified.
BP4	Met	Multiple lines of computational evidence support a benign effect: REVEL score 0.325 (below 0.5 pathogenic threshold), BayesDel score 0.081 (well below damaging threshold), and SpliceAI max delta score 0.00 (no predicted splicing impact). Three independent in silico tools consistently predict a tolerated/benign effect.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case where an alternate molecular basis for disease was identified was available.
BP6	Not met	ClinVar reports this variant as Likely benign (1-star, criteria provided, single submitter — Labcorp/Invitae). Per adjudication rules, BP6 at supporting benign is only automatically applied for 3-star expert panel classifications. A single submitter does not meet this threshold.	clinvar
BP7	N/A	NM_003620.3:c.1525G>C is a missense variant (p.Asp509His), not a synonymous/silent substitution. BP7 applies only to synonymous variants without predicted splice impact.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a single nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders; PPM1D is not established as a recessive disease gene.
PM4	N/A	PM4 applies to protein length changes from in-frame indels or stop-loss; this variant is a single nucleotide substitution (missense).

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