About PPM1D
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPM1D c.1525G>C, p.(Asp509His)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
139 / 1,613,978 alleles
gnomAD v4.1: 139 / 1,613,978 alleles. Recorded AF 8.61226e-05. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Likely benign. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PPM1D, a protein phosphatase, is altered by mutation in various solid and hematologic malignancies including in therapy-related hematopoietic disorder
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 2
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- gnomAD v4.1: AF = 0.0086% (139/1
- 613
- 978 alleles
- 0 homozygotes)
- grpmax FAF = 0.0096%.
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.325 (tolerated/benign range).
- BayesDel: 0.081 (tolerated).
- SpliceAI: delta 0.00 (no splice alteration).
Sources
Not met · 22 · evaluated, threshold not reached
PS1 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. Details ▾Hide ▴
Evidence considered
- No established pathogenic variant with same amino acid change found.
PS2 No de novo observation with confirmed parentage was identified for this variant in the available literature or databases. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No trio or de novo sequencing data reviewed.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: no variant-specific functional evidence. COSMIC: no somatic entries. No literature reports for this variant.
Still missing
- No functional studies available for this missense variant.
Sources
PS4 No case-control or cohort enrichment data comparing affected versus control populations was identified for this variant. Details ▾Hide ▴
Evidence considered
- No prevalence or case-control data available.
Still missing
- No affected vs. control comparison data.
PM1 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. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: no significant hotspot at D509. Residue not in a statistically enriched mutational cluster.
PM5 No same-residue (D509) alternative pathogenic missense variant was identified. PM5 candidate harvesting was unable to confirm classic same-residue comparators in ClinVar. Details ▾Hide ▴
Evidence considered
- No pathogenic same-residue comparator identified at D509.
Still missing
- Manual ClinVar search not performed for D509 comparator variants.
PM6 No de novo observation (with or without confirmed parentage) was identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No trio sequencing data reviewed.
PP1 No cosegregation data with disease in affected family members was identified for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation studies.
PP2 HCI prior probability is not available for PPM1D. Without gene-level missense constraint data (e.g., Z-score), PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- HCI prior not supported for PPM1D
- no constraint data available.
Still missing
- No gene-level missense constraint metrics.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.325 (benign range).
- BayesDel: 0.0808 (tolerated).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
PP4 No phenotype or family history data specific to a PPM1D-associated disorder was available for the proband harboring this variant. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data available.
Still missing
- No proband phenotype or clinical information.
PP5 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. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign
- 1-star (criteria provided
- single submitter — Labcorp/Invitae). Not 3-star EP.
Sources
BA1 gnomAD v4.1 allele frequency is 0.0086%, well below the 1% BA1 threshold. Details ▾Hide ▴
BS1 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. Details ▾Hide ▴
BS2 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. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data.
Still missing
- No control cohort data with age-at-observation.
BS3 No variant-specific functional studies demonstrating a benign effect for NM_003620.3:c.1525G>C were identified in the literature or curated databases. Details ▾Hide ▴
Evidence considered
- No functional studies testing this variant for benign effect.
Still missing
- No experimental functional data for this variant.
BS4 No nonsegregation data (variant absent in affected family members) was available for this variant. Details ▾Hide ▴
Evidence considered
- No nonsegregation data.
Still missing
- No family segregation data.
BP1 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. Details ▾Hide ▴
Evidence considered
- PMID:27401275 reports missense PPM1D variants (c.1607G>A
- p.Arg536Lys) as potentially disease-associated germline mutations.
BP2 No observation of this variant in trans with a known pathogenic PPM1D variant was identified. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
BP5 No observation of this variant in a case where an alternate molecular basis for disease was identified was available. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data.
Still missing
- No data on co-occurring pathogenic variants in other genes.
BP6 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. Details ▾Hide ▴
Evidence considered
- ClinVar: Likely benign
- 1-star
- single submitter. Does not meet 3-star EP threshold for BP6 supporting benign.
Sources
PS5 No alternative nucleotide change at c.1525 resulting in the same amino acid change (p.Asp509His) has been established as pathogenic. Details ▾Hide ▴
Evidence considered
- No established pathogenic variant from an alternate nucleotide change at this codon.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense substitution does not qualify for PVS1 under ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
PM3 N/APM3 applies to recessive disorders; PPM1D is not established as a recessive disease gene. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from in-frame indels or stop-loss; this variant is a single nucleotide substitution (missense). Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a single nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
- BP7 not applicable.
Identifiers
- Gene
- PPM1D
- Transcript
- NM_003620.3
- Coding (HGVS c.)
- NM_003620.3:c.1525G>C
- Protein (HGVS p.)
- NP_003611.1:p.(Asp509His)
- GRCh38
- chr17:60663259 G>C
- GRCh37
- chr17:58740620 G>C
- ClinVar
- 2170443
Gene diagram
Every interpreted variant in PPM1D, mapped onto the exon structure of NM_003620.3. Select a row to find it on the plot.
PPM1DNM_003620.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PPM1D
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
139 / 1,613,978 alleles
AF 8.61e-05 · 0 homozygotes · FAF 9.61e-05
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 8.6e-05 · 139 / 1,613,978 alleles · 0 hom · FAF 9.6e-05
| European (non-Finnish)132 / 1,180,030 | 0.00011 |
| Admixed American3 / 59,982 | 5e-05 |
| Remaining individuals3 / 62,480 | 4.8e-05 |
| African/African American1 / 74,900 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.61226e-05; MAF= 0.00861%, 139/1613978 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000111862; MAF= 0.01119%, 132/1180030 alleles, homozygotes = 0); grpmax FAF= 9.607e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.325
- BayesDel
- 0.081
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.325 (tolerated/benign range).
- BayesDel: 0.081 (tolerated).
- SpliceAI: delta 0.00 (no splice alteration).
Sources
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.325 (benign range).
- BayesDel: 0.0808 (tolerated).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous
- BP7 not applicable.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.325. BayesDel score = 0.0808168.
1 paper record listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Describes the Sherloc refinement of the ACMG-AMP variant classification framework. This is a methods paper that does not report on any specific PPM1D variants. NM_003620.3:c.1525G>C is not mentioned.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
139 / 1,613,978 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2170443/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-58740620-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-60663259-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-60663259-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003620.3%3Ac.1525…
- OncoKB ↗www.oncokb.org/gene/PPM1D/D509H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PPM1D+c.1525G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.61226e-05; MAF= 0.00861%, 139/1613978 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000111862; MAF= 0.01119%, 132/1180030 alleles, homozygotes = 0); grpmax FAF= 9.607e-05.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 2170443)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.325. BayesDel score = 0.0808168.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PPM1D, a protein phosphatase, is altered by mutation in various solid and hematologic malignancies including in therapy-related hematopoietic disorder
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.