About PPM1D
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPM1D c.1473dup, p.(Asn492Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Strong
PS3 · strong
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.
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PM1 moderate, PM2 supporting; combination = 1 strong + 1 moderate + 1 supporting, which maps to Likely Pathogenic.
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
0 / 1,614,190 alleles
gnomAD v4.1: 0 / 1,614,190 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from 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.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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: 3 met · 13 not met · 0 not assessed · 13 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.1473dupT (p.Asn492Ter) is a nonsense variant in exon 6 of PPM1D that truncates the protein within the C-terminal degradation domain.
This variant is absent from gnomAD v4.1 (0/1,614,190 alleles), satisfying PM2 at supporting level.
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).
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).
OncoKB classifies p.N492* as Likely Oncogenic with Likely Gain-of-function biological effect.
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.
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.
Overall classification: Likely Pathogenic based on PS3 (strong), PM1 (moderate), and PM2 (supporting) according to ACMG/AMP 2015 combination rules (1 strong + 1 moderate).
No criteria match.
Met · 3
PS3 StrongThe 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. Details ▾Hide ▴
Evidence considered
- CRISPR-Cas9 tiling screen (265 gRNAs across PPM1D) in PMID:29954749 shows truncating mutations in aa 400-585 confer chemoresistance
- N492 falls within this systematically characterized range
- PMID:24880341 demonstrates exon 6 truncating mutations enhance ability to suppress Chk2 phosphorylation (gain-of-function)
- PMID:25742468 confirms truncating exon 6 mutations code for gain-of-function PPM1D with retained phosphatase activity
- PMID:23907125 characterizes truncating mutations at E525 and R552 showing altered protein stability
- OncoKB classifies as Likely Gain-of-function
- Likely Oncogenic
Still missing
- Exact variant N492* has not been individually tested in a functional assay
- evidence is from systematic range characterization
Sources
PM1 Moderatep.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. Details ▾Hide ▴
Evidence considered
- Variant truncates PPM1D within the C-terminal degradation domain (exon 6
- aa ~400-605)
- Loss of this domain results in hyperstable protein with enhanced phosphatase activity (PMID:29954749)
- Domain functionally characterized as critical for proteasomal degradation across multiple studies
Sources
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (0/1
- 614
- 190 alleles
- AF=0)
- Absent from gnomAD v2.1
Sources
Not met · 13 · evaluated, threshold not reached
PVS1 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. Details ▾Hide ▴
Evidence considered
- Nonsense variant predicted to produce p.Asn492Ter in exon 6 of PPM1D
- Truncating PPM1D exon 6 mutations are gain-of-function via loss of C-terminal degradation domain (PMID:29954749
- PMID:24880341
- PMID:25742468)
- OncoKB classifies as Likely Gain-of-function
- Likely Oncogenic
Sources
PMID:23907125 ↗PMID:24880341 ↗PMID:25742468 ↗PMID:29954749 ↗oncokb ↗pvs1_gene_contextpvs1_variant_assessment
PS2 No de novo report for NM_003620.3:c.1473dupT was identified in any publication reviewed. Details ▾Hide ▴
Still missing
- No de novo testing data available
PS4 No case-control study or significant enrichment data for NM_003620.3:c.1473dupT was identified in the reviewed literature. Details ▾Hide ▴
Still missing
- No variant-specific case-control or enrichment data available
PP1 No segregation data for NM_003620.3:c.1473dupT was identified in any reviewed publication. Details ▾Hide ▴
Still missing
- No segregation data available
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no predicted splice alteration
- REVEL and BayesDel not applicable for duplication variant type
Sources
PP4 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. Details ▾Hide ▴
Still missing
- No proband phenotype data available
PP5 NM_003620.3:c.1473dupT is absent from ClinVar; no reputable source has classified this variant as pathogenic. PP5 requires a reputable source classification. Details ▾Hide ▴
BA1 Variant is absent from gnomAD (0/1,614,190 alleles). BA1 requires allele frequency >1% in population databases. Details ▾Hide ▴
BS1 Variant is absent from gnomAD (0/1,614,190 alleles). BS1 requires allele frequency >0.3% in population databases under generic ACMG. Details ▾Hide ▴
BS3 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. Details ▾Hide ▴
No further detail was recorded.
BP3 Not an in-frame deletion/insertion in a repetitive region without known function. BP3 does not apply to nonsense variants. Details ▾Hide ▴
No further detail was recorded.
BP4 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. Details ▾Hide ▴
BP7 Not a synonymous variant. BP7 does not apply to nonsense/frameshift variants. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot an SNV with a previously established pathogenic amino acid change at the same position. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ANot an in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AUnable to confirm classic same-residue PM5 semantics; this is a nonsense variant and no comparator missense at N492 was identified for PM5 evaluation. Details ▾Hide ▴
Evidence considered
- pm5_candidates artifact found no same-residue candidates for PM5 comparison
PM6 N/ANo de novo report for this variant identified; PM6 requires a confirmed de novo observation. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP2 N/APP2 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. Details ▾Hide ▴
No further detail was recorded.
BS2 N/ANo observation in healthy adults with full penetrance expected at early age identified. No homozygous or hemizygous data available. Details ▾Hide ▴
No further detail was recorded.
BS4 N/ANo segregation data available to assess lack of segregation in affected family members. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 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. Details ▾Hide ▴
No further detail was recorded.
BP2 N/ANo observation in trans with a pathogenic variant identified. No data available for BP2 evaluation. Details ▾Hide ▴
No further detail was recorded.
BP5 N/AVariant is absent from ClinVar; no reputable source classification as benign or likely benign exists. Details ▾Hide ▴
BP6 N/AVariant is absent from ClinVar; no reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
PS5 N/ANot an SNV with a validated functional assay demonstrating a deleterious effect through an experimentally established functional study. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PPM1D
- Transcript
- NM_003620.3
- Coding (HGVS c.)
- NM_003620.3:c.1473dup
- Protein (HGVS p.)
- NP_003611.1:p.(Asn492Ter)
- GRCh38
- chr17:60663206 A>AT
- GRCh37
- chr17:58740567 A>AT
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
0 / 1,614,190 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,614,190 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1614190 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75058 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00
- no predicted splice alteration
- REVEL and BayesDel not applicable for duplication variant type
Sources
BP4 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. Details ▾Hide ▴
BP7 Not a synonymous variant. BP7 does not apply to nonsense/frameshift variants. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
5 paper records listed. 3 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
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PMID 24880341 ↗Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.Identifies somatic truncating PPM1D mutations in exon 6 in 37.5% of brainstem gliomas harboring H3F3A K27M mutations. Functional characterization shows these truncating mutations enhance PPM1D-mediated suppression of Chk2 phosphorylation, demonstrating gain-of-function. The specific variant p.Asn492Ter was not individually identified or studied.→ PS3 → PM1 Does not name this variant
Source detail
PPM1D mutations were truncating alterations in exon 6 that enhanced the ability for PPM1D to suppress the activation of DNA damage response checkpoint protein Chk2.
Location Introductory Paragraph; Results (Fig. 1)
Context Exome sequencing of brainstem and thalamic gliomas; in vitro functional assays of PPM1D truncating mutations on Chk2 phosphorylation
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PMID 25742468 ↗Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients.Describes truncating PPM1D mutations (nonsense and frameshift) in exon 6 found in blood DNA of lung cancer patients. Reports these mutations as gain-of-function with retained phosphatase activity, and contextualizes them as mosaic rather than true germline. The specific variant p.Asn492Ter was not identified or studied.→ PS3 → PM1 Does not name this variant
Source detail
These mutants code for gain-of-function PPM1D with retained phosphatase activity.
Location Introduction/Background section
Context Sequencing of exon 6 in blood DNA from lung cancer patients; functional characterization of truncating mutations
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PMID 29954749 ↗PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells.Demonstrates that truncating PPM1D mutations in exon 6 confer chemotherapy resistance and selective expansion of hematopoietic cells via a gain-of-function mechanism (loss of C-terminal degradation domain, hyperstable protein, enhanced phosphatase activity). A CRISPR-Cas9 tiling screen of 265 gRNAs identified amino acids 400-585 as the critical region where truncating mutations produce the chemoresistance phenotype. N492 falls within this systematically characterized range. The specific variant p.Asn492Ter was not individually tested.→ PS3 → PM1 Does not name this variant
Source detail
After treating the transduced cells for 24 days with cytarabine, we observed a selective outgrowth of cells carrying gRNAs targeting amino acids 400 – 585.
Location Results: 'In vitro chemotherapy treatment selects for the same PPM1D mutations identified in patient samples'; Fig. 2A; Discussion
Context CRISPR-Cas9 tiling screen in Molm13 leukemia cells; competition assays; proteasome degradation reporter; phosphoproteomic mass spectrometry; in vivo mouse transplantation
Other recorded publications
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PMID 23907125 ↗Genetic variants and mutations of PPM1D control the response to DNA damage.Characterizes Wip1 (PPM1D) missense variants L120F, P322Q, and I496V as dominant-negative, and truncating mutations E525X and R552X in primary human cancers. E525X is gain-of-function (increased protein stability); R552X is loss-of-function (highly unstable). The study concludes that PPM1D truncating mutations in the C-terminus can be gain-of-function, but the specific variant p.Asn492Ter (c.1473dupT) was not studied or mentioned.Does not name this variant
Quoted passage
Truncating mutations in the C terminus of Wip1 have been reported as gain-of-function mutations.
Results, Table 2 (PPM1D mutations in human cancers); Discussion
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PMID 30304655 ↗Classification and Personalized Prognosis in Myeloproliferative Neoplasms.A genomic classification study of 2,035 patients with myeloproliferative neoplasms, sequencing 69 myeloid cancer genes including PPM1D. Provides broad genomic landscape context but does not specifically discuss the variant p.Asn492Ter or any individual PPM1D truncating mutation.Does not name this variant
Quoted passage
We sequenced coding exons from 69 myeloid cancer genes in patients with myeloproliferative neoplasms.
Introduction, Methods
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,614,190 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
Captured ClinVar source record
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/?term=NM_003620.3%3Ac.1473dupT
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-58740567-A-AT?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-60663206-A-AT?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-60663206-A-AT
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003620.3%3Ac.1473…
- OncoKB ↗www.oncokb.org/gene/PPM1D/N492*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PPM1D+c.1473dup
- 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= 0; MAF= 0.00000%, 0/1614190 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75058 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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.