PPM1Dc.1535delLikely pathogenic

Print report

Variant interpretation report

PPM1D c.1535del, p.(Asn512IlefsTer2)

NM_003620.3:c.1535del NP_003611.1:p.(Asn512IlefsTer2) View identifiers

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.

About PPM1D

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 moderate (pathogenic) · 4 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 4 Pathogenic
Pipeline record: 14 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

PVS1 (supporting): 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.
PM1 (moderate): 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.
PM2 (supporting): 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).
PM6 (supporting): 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.
PP5 (supporting): 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.

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: 5 Benign evidence criteria: 0

Pathogenic criteria applied · 5

PVS1Supporting

PVS1 · supporting

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.

PM1Moderate

PM1 · moderate

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.

PM2Supporting

PM2 · supporting

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).

PM6Supporting

PM6 · supporting

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.

PP5Supporting

PP5 · supporting

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.

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: PVS1 supporting, PM1 moderate, PM2 supporting, PM6 supporting, PP5 supporting; combination = 1 moderate + 4 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

9 / 1,613,852 alleles

gnomAD v4.1: 9 / 1,613,852 alleles. Recorded AF 5.57672e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.19523e-05; MAF= 0.00120%, 3/250998 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26755e-05; MAF= 0.00327%, 1/30604 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

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

4 reported laboratory submissions

4 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · PP5 → 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.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

33 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV59954107, n = 33 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 5 met · 15 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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).

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).

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.

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).

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).

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.

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).

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

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.

Met · 5

PVS1 SupportingThis 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. Details ▾Hide ▴

Evidence considered

Frameshift variant in exon 6 producing p.Asn512IlefsTer2
predicted to truncate the protein after 2 amino acids
Last exon location precludes nonsense-mediated decay
C-terminal truncations of PPM1D are established gain-of-function mutations (PMID:23907125
PMID:24880341
PMID:25742468
PMID:29954749)
Loss of C-terminal degradation domain increases protein stability and phosphatase activity

Still missing

Uncertainty about whether gain-of-function PPM1D truncations should receive any PVS1 credit under germline ACMG framework

Sources

pvs1_gene_contextpvs1_variant_assessmentPMID:23907125 ↗PMID:24880341 ↗PMID:25742468 ↗PMID:29954749 ↗

PM1 ModerateThis 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. Details ▾Hide ▴

Evidence considered

PPM1D C-terminal domain (exon 6) is a well-characterized functional domain containing a degradation signal
PMID:23907125 demonstrated that C-terminal truncations alter protein stability and activity
PMID:24880341 reported that exon 6 truncating mutations are gain-of-function in brainstem gliomas
PMID:25742468 showed exon 6 truncations produce hyperstable WIP1 with gain-of-function
PMID:29954749 demonstrated that loss of C-terminal degradation domain leads to increased PPM1D expression and chemoresistance
Variant truncates at position 512
removing C-terminal 94 amino acids

Sources

PMID:23907125 ↗PMID:24880341 ↗PMID:25742468 ↗PMID:29954749 ↗

PM2 SupportingThis 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). Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.0012% (3/250
998)
grpmax FAF=2.93e-06
gnomAD v4.1: AF=0.00056% (9/1
613
852)
grpmax FAF=2.47e-06
gnomAD-Canada: absent
No homozygotes observed in any database

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PM6 SupportingOne 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. Details ▾Hide ▴

Evidence considered

ClinVar SCV001499843 (Undiagnosed Diseases Network
NIH): origin reported as de novo
classification Pathogenic
No peer-reviewed publication confirming de novo status with parentage verification

Still missing

No published case report confirming de novo occurrence with clinical phenotype details
Maternity and paternity not confirmed

Sources

clinvar ↗

PP5 SupportingThis 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. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 817626: Pathogenic
4 clinical laboratories: Mendelics
UDN/NIH
GeneDx
Greenwood Genetic Center
Review status: criteria provided
single submitter

Still missing

Evidence used by clinical laboratories not publicly available for independent verification

Sources

clinvar ↗

Not met · 15 · evaluated, threshold not reached

PS2 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. Details ▾Hide ▴

Evidence considered

ClinVar SCV001499843 reports origin as de novo from Undiagnosed Diseases Network
NIH
No published case report with parentage confirmation available

Still missing

No peer-reviewed publication documenting de novo occurrence with confirmed maternity and paternity

Sources

clinvar ↗

PS3 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. Details ▾Hide ▴

Evidence considered

PMID:23907125 tested E525X and R552X truncations
demonstrating gain-of-function for E525X and loss-of-function for R552X
PMID:24880341 identified somatic PPM1D exon 6 truncations in brainstem gliomas with gain-of-function properties
PMID:25742468 demonstrated gain-of-function for exon 6 truncating mutations in lung cancer patients
PMID:29954749 used CRISPR to create exon 6 frameshift mutations showing chemoresistance and gain-of-function via protein stabilization
None of these studies directly tested or reported c.1535del (p.Asn512IlefsTer2)

Still missing

No experimental data directly testing c.1535del
Position 512 is not within a systematically characterized range (tiling/saturation/truncation series) in any study

Sources

PMID:23907125 ↗PMID:24880341 ↗PMID:25742468 ↗PMID:29954749 ↗

PS4 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. Details ▾Hide ▴

Evidence considered

ClinVar reports variant as Pathogenic in 4 clinical laboratories but provides no case-control statistics

Still missing

No case-control enrichment data available

Sources

clinvar ↗

PP1 No cosegregation data with disease in multiple affected family members is available. Details ▾Hide ▴

Still missing

No family segregation data available

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI: max delta score 0.00 (no predicted splice impact)
REVEL: not available (not an SNV)
BayesDel: not available (not an SNV)
HCI prior: gene not supported

Still missing

No in silico tools applicable for frameshift variants

Sources

spliceai ↗

PP4 No patient phenotype or family history information is available in any of the reviewed sources to assess phenotypic specificity. Details ▾Hide ▴

Still missing

No proband phenotype or family history provided

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max subpopulation AF: 0.00327% (South Asian)
gnomAD v4.1 max subpopulation AF: 0.00134% (African/African American)
All AFs well below 1% BA1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 Maximum allele frequency in any population is 0.00327% (South Asian, gnomAD v2.1), well below the 0.3% BS1 threshold. Details ▾Hide ▴

Evidence considered

All population AFs < 0.004%
far below 0.3% BS1 threshold

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No data available on observation of this variant in healthy adults where full penetrance would be expected at an early age. Details ▾Hide ▴

Still missing

No healthy adult carrier data available

BS3 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. Details ▾Hide ▴

Evidence considered

PMID:29954749: exon 6 truncations increase PPM1D protein stability and confer chemoresistance
PMID:25742468: exon 6 truncations produce hyperstable WIP1 with retained phosphatase activity
PMID:24880341: exon 6 truncations are gain-of-function and mutually exclusive with TP53 mutations in brainstem gliomas
PMID:23907125: C-terminal truncations alter protein stability with functional consequences

Sources

PMID:23907125 ↗PMID:24880341 ↗PMID:25742468 ↗PMID:29954749 ↗

BS4 No segregation data in affected family members is available to assess lack of segregation. Details ▾Hide ▴

Still missing

No family segregation data available

BP2 No data available on observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴

Still missing

No trans-configuration data available

BP4 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. Details ▾Hide ▴

Evidence considered

SpliceAI: max delta 0.00 (no splice impact)
REVEL/BayesDel/HCI prior: not available for non-SNV variant

Still missing

Insufficient in silico evidence for BP4
only SpliceAI available

Sources

spliceai ↗

BP5 No data available indicating this variant was found in a case with an established alternate molecular basis for disease. Details ▾Hide ▴

Still missing

No alternate molecular basis data available

BP6 ClinVar reports this variant as Pathogenic, not benign. BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴

Evidence considered

ClinVar classification: Pathogenic (4 clinical laboratories)

Sources

clinvar ↗

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to same amino acid change via different nucleotide change. Not applicable to frameshift variants. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This is a frameshift deletion, not an in-frame change. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴

Evidence considered

pm5_candidates.json confirmed not_applicable: unable to confirm classic same-residue PM5 semantics for this frameshift variant

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes with low rate of benign missense variation. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is itself a truncating variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 applies to a different nucleotide change resulting in the same missense amino acid change as a known pathogenic variant. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: PPM1D
Transcript: NM_003620.3
Coding (HGVS c.): NM_003620.3:c.1535del
Protein (HGVS p.): NP_003611.1:p.(Asn512IlefsTer2)
GRCh38: chr17:60663262 CA>C
GRCh37: chr17:58740623 CA>C
ClinVar: 817626
COSMIC: COSV59954107

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 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 9 / 1,613,852 alleles AF 5.58e-06 · 0 homozygotes · FAF 2.47e-06

gnomAD v2.1 3 / 250,998 alleles AF 1.2e-05 · 0 homozygotes · FAF 2.93e-06

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 5.6e-06 · 9 / 1,613,852 alleles · 0 hom · FAF 2.5e-06

African/African American1 / 74,888	1.3e-05
South Asian1 / 91,074	1.1e-05
European (non-Finnish)7 / 1,179,966	5.9e-06

0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.

gnomAD v2.1

AF 1.2e-05 · 3 / 250,998 alleles · 0 hom · FAF 2.9e-06

South Asian1 / 30,604	3.3e-05
European (non-Finnish)2 / 113,438	1.8e-05

0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.57672e-06; MAF= 0.00056%, 9/1613852 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33533e-05; MAF= 0.00134%, 1/74888 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -267 bp

0.000

SpliceAI acceptor gainat -255 bp

0.000

SpliceAI donor lossat -402 bp

0.000

SpliceAI donor gainat -211 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI: max delta score 0.00 (no predicted splice impact)
REVEL: not available (not an SNV)
BayesDel: not available (not an SNV)
HCI prior: gene not supported

Still missing

No in silico tools applicable for frameshift variants

Sources

spliceai ↗

Evidence considered

SpliceAI: max delta 0.00 (no splice impact)
REVEL/BayesDel/HCI prior: not available for non-SNV variant

Still missing

Insufficient in silico evidence for BP4
only SpliceAI available

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

8 paper records listed. 4 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

Genetic variants and mutations of PPM1D control the response to DNA damage.

Characterized missense genetic variants (L120F, P322Q, I496V) and somatic cancer mutations (E525X, R552X hotspots) in PPM1D/Wip1. Demonstrated that C-terminal truncations can be gain-of-function (E525X: increased protein stability, enhanced suppression of ATM/Chk2 signaling) or loss-of-function (R552X: unstable protein). NM_003620.3:c.1535del (p.Asn512IlefsTer2) was not specifically tested or reported.
→ PVS1 → PM1 Does not name this variant
PMID 23907125 ↗
Source detail

Truncating mutations in the C terminus of Wip1 have been reported as gain-of-function mutations.

Location Results; Table 2; Figure 4

Context HeLa cells, 293T cells; phosphatase activity assays, cycloheximide stability assays, colony formation assays
Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

Identified somatic PPM1D exon 6 truncating mutations in 37.5% of H3F3A K27M-mutant brainstem gliomas. Demonstrated these mutations are gain-of-function, enhancing PPM1D's ability to suppress Chk2 activation. NM_003620.3:c.1535del was not among the specific mutations tested.
→ PVS1 → PM1 Does not name this variant
PMID 24880341 ↗
Source detail

The 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

Context Whole exome sequencing of brainstem and thalamic gliomas; in vitro functional assays
Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients.

Identified truncating PPM1D exon 6 mutations in blood DNA of lung cancer patients. Demonstrated that truncating mutations code for gain-of-function PPM1D with retained phosphatase activity and hyperstable protein. NM_003620.3:c.1535del was not specifically reported among the mutations identified.
→ PVS1 → PM1 Does not name this variant
PMID 25742468 ↗
Source detail

The truncating mutations code for hyper-stable WIP1 protein, which induces strong dephosphorylation of Ser15 of p53 and impairs the p53-dependent G1 checkpoint.

Location Abstract; Introduction; Results

Context Blood DNA from lung cancer patients; U-2 OS and HCT116 cell lines; p53 signaling assays
PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells.

Demonstrated that truncating PPM1D exon 6 mutations confer chemotherapy resistance through loss of a C-terminal degradation domain, leading to increased PPM1D protein stability and gain-of-function. Used CRISPR-Cas9 tiling screen to show that mutations between amino acids 400-585 produce the chemoresistance phenotype. Position 512 falls within this characterized range. NM_003620.3:c.1535del was not specifically reported as a patient mutation but the functional characterization of the 400-585 range is relevant.
→ PVS1 → PM1 Does not name this variant
PMID 29954749 ↗
Source detail

This region tightly overlaps with the region of PPM1D that is mutated in CHIP and t-MNs, implying that the PPM1D mutations identified in patients result in a chemotherapy resistance phenotype.

Location Abstract; Results (CRISPR Screen); Figures 1-2

Context Molm13 AML cell line; CRISPR-Cas9 mutagenesis screen; in vivo mouse hematopoietic transplantation; phosphoproteomic mass spectrometry

Other recorded publications

Classification and Personalized Prognosis in Myeloproliferative Neoplasms.

Genomic characterization study of myeloproliferative neoplasms (MPNs) sequencing 69 myeloid cancer genes. PPM1D is mentioned in the gene panel but NM_003620.3:c.1535del is not reported or discussed in this paper.
Does not name this variant
PMID 30304655 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

ACMG/AMP standards and guidelines for sequence variant interpretation. This is the foundational methodological paper describing the variant classification framework. Does not discuss PPM1D or this specific variant.
Does not name this variant
PMID 25741868 ↗
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.

St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Focuses on breast cancer treatment recommendations. Does not discuss PPM1D or this variant.
Does not name this variant
PMID 34242744 ↗
BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.

Adam MP et al. · 1993

BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer GeneReview. Discusses BRCA1/BRCA2-associated cancer syndromes. Does not discuss PPM1D or this variant.
Does not name this variant
PMID 20301425 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 9 / 1,613,852 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 4 Pathogenic 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories). (ClinVarID = 817626)

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 previously been reported in somatic cancers (COSMIC; COSV59954107, n = 33 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.