About PPM1D
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPM1D c.1613del, p.(Leu538Ter)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong
This nonsense variant is predicted to truncate the PPM1D protein at p.(Leu538Ter). Generic PVS1 review is allowed because germline loss of function is considered an established disease mechanism for PPM1D, but distal truncating variants require caution under the ClinGen SVI PVS1 framework, so a downgraded PVS1 strength is more appropriate than full-strength PVS1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 at AF 6.19495e-07 (0.00006%, 1/1614218 alleles), which is below the 0.1% rarity threshold and supports PM2.
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.
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
1 / 1,614,218 alleles
gnomAD v4.1: 1 / 1,614,218 alleles. Recorded AF 6.19495e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
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.
28 criteria with recorded statuses: 2 met · 4 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The PPM1D NM_003620.3:c.1613del (NP_003611.1:p.(Leu538Ter), p.(L538*)) variant has been observed in somatic cancer resources as a variant-specific likely oncogenic truncating alteration and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (AF 6.19495e-07; 1/1614218 alleles), which is below the 0.1% rarity threshold and supports a rarity-based criterion.
Experimental studies of terminal truncating PPM1D variants show increased protein stability or activity and altered DNA-damage-response signaling, but the available studies do not directly test p.(Leu538Ter).
Generic PVS1 review is permitted because germline loss of function is considered an established disease mechanism for PPM1D, although distal truncating variants require manual review for appropriate strength assignment.
No criteria match.
Met · 2
PVS1 StrongThis nonsense variant is predicted to truncate the PPM1D protein at p.(Leu538Ter). Generic PVS1 review is allowed because germline loss of function is considered an established disease mechanism for PPM1D, but distal truncating variants require caution under the ClinGen SVI PVS1 framework, so a downgraded PVS1 strength is more appropriate than full-strength PVS1. Details ▾Hide ▴
Rule
Generic ACMG fallback using ClinGen SVI PVS1 recommendations
Evidence considered
- PPM1D was flagged as eligible for generic PVS1 review.
- The variant-level scaffold identifies NM_003620.3:c.1613del as a nonsense variant with default PVS1 consideration and notes possible downgrade for distal truncation.
Still missing
- Transcript relevance and the effect of this distal truncation on nonsense-mediated decay should be confirmed before final classification.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 at AF 6.19495e-07 (0.00006%, 1/1614218 alleles), which is below the 0.1% rarity threshold and supports PM2. Details ▾Hide ▴
Rule
Population rarity threshold <0.1%
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: 1 allele
- AF 6.19495e-07
- no homozygotes.
Sources
Not met · 4 · evaluated, threshold not reached
PM1 Available hotspot review did not identify this variant in a statistically significant hotspot, so current evidence does not support PM1. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review did not show a significant hotspot at this residue.
Still missing
- Hotspot review was flagged for human review.
Sources
BA1 The observed population frequency is far below the benign stand-alone threshold: gnomAD v4.1 AF is 6.19495e-07 (0.00006%), which is below the 1% BA1 threshold. Details ▾Hide ▴
Rule
Benign stand-alone threshold >1%
Evidence considered
- gnomAD v4.1 AF 6.19495e-07
- 1/1614218 alleles.
Sources
BS1 The observed population frequency does not exceed the strong benign threshold: gnomAD v4.1 AF is 6.19495e-07 (0.00006%), which is below the 0.3% BS1 threshold. Details ▾Hide ▴
Rule
Strong benign threshold >0.3%
Evidence considered
- gnomAD v4.1 AF 6.19495e-07
- 1/1614218 alleles.
Sources
BS3 Available functional studies do not show normal PPM1D function for this class of truncating variants; instead they report abnormal increased activity or altered stress-response signaling, so BS3 is not supported. Details ▾Hide ▴
Evidence considered
- Published functional studies of related truncating PPM1D variants report abnormal effects rather than normal function.
Still missing
- No benign functional study for this variant was identified.
Sources
Not assessed · 15 · no assessment recorded
PS1 No evidence was identified showing a different nucleotide change already established as pathogenic for the same protein consequence. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no result for this variant.
Still missing
- No same-amino-acid pathogenic comparator was identified in the available sources.
Sources
PS2 No confirmed de novo data with parental testing were identified. Details ▾Hide ▴
Still missing
- Parental testing and phenotype details were not available.
PS3 Available functional studies show that truncating PPM1D variants in the terminal region can increase protein stability or activity and alter DNA-damage-response signaling, but the retrieved studies do not directly test p.(Leu538Ter), so PS3 cannot be applied from the current evidence alone. Details ▾Hide ▴
Evidence considered
- Functional literature supports abnormal effects for related terminal truncating PPM1D variants.
- No assay specific to p.(Leu538Ter) was identified.
Still missing
- No well-established functional study directly testing NM_003620.3:c.1613del was identified.
Sources
PS4 No case-control or statistically enriched germline case series were identified for this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar has no submission for this variant.
Still missing
- No germline prevalence data comparing affected and control cohorts were available.
Sources
PM3 No data were identified showing this variant in trans with another pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
- Phase and second-allele data were not available.
PM6 No assumed de novo occurrence without full parental confirmation was identified. Details ▾Hide ▴
Still missing
- Family testing data were not available.
PP1 No segregation data were identified. Details ▾Hide ▴
Still missing
- Family segregation information was not available.
PP4 No phenotype information was provided that would allow assessment of a highly specific PPM1D-related clinical presentation. Details ▾Hide ▴
Still missing
- Clinical phenotype details were not available.
PP5 No reputable pathogenic classification from an external clinical database was identified because this variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no result.
Still missing
- No ClinVar submission was available.
Sources
BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency expected to argue against pathogenicity. Details ▾Hide ▴
Evidence considered
- No homozygotes were observed in gnomAD v4.1.
Still missing
- Well-phenotyped unaffected carrier data were not available.
Sources
BS4 No data were identified showing lack of segregation with disease in a family. Details ▾Hide ▴
Still missing
- Family segregation data were not available.
BP2 No phase data were identified to show this variant in cis with a pathogenic variant or in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- Phase and co-occurrence data were not available.
BP3 No evidence was identified showing that this variant lies in a repetitive region without known function. Details ▾Hide ▴
Still missing
- Repeat-region and low-complexity context were not specifically established.
BP5 No alternate molecular explanation was provided that would account for the phenotype independently of this variant. Details ▾Hide ▴
Still missing
- Clinical and broader genotype context were not available.
BP6 No reputable benign classification from an external clinical database was identified because this variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no result.
Still missing
- No ClinVar submission was available.
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/APM4 is not applicable because this is a nonsense variant already evaluated under the loss-of-function framework rather than an in-frame length-changing variant. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
PM5 N/APM5 is not applicable because this criterion is for novel missense changes at a residue with a different pathogenic missense change, and this variant is a nonsense change. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
PP2 N/APP2 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
PP3 N/APP3 is not applicable because this variant is a nonsense deletion with a direct predicted truncating effect, so missense or splice prediction algorithms are not the primary evidence source for interpretation. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
BP1 N/ABP1 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
BP4 N/ABP4 is not applicable because this variant is a nonsense deletion and not a missense or synonymous change suited to benign computational prediction frameworks. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor an intronic change outside the canonical splice region. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
Identifiers
- Gene
- PPM1D
- Transcript
- NM_003620.3
- Coding (HGVS c.)
- NM_003620.3:c.1613del
- Protein (HGVS p.)
- NP_003611.1:p.(Leu538Ter)
- GRCh38
- chr17:60663345 AT>A
- GRCh37
- chr17:58740706 AT>A
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
1 / 1,614,218 alleles
AF 6.19e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,218 alleles · 0 hom
| European (non-Finnish)1 / 1,180,032 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19495e-07; MAF= 0.00006%, 1/1614218 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47435e-07; MAF= 0.00008%, 1/1180032 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable because this variant is a nonsense deletion with a direct predicted truncating effect, so missense or splice prediction algorithms are not the primary evidence source for interpretation. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
BP4 N/ABP4 is not applicable because this variant is a nonsense deletion and not a missense or synonymous change suited to benign computational prediction frameworks. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor an intronic change outside the canonical splice region. Details ▾Hide ▴
Evidence considered
- Variant-level scaffold identifies a nonsense change.
Sources
pvs1_variant_assessment
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,614,218 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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.1613del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-58740706-AT-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-60663345-AT-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003620.3%3Ac.1613…
- OncoKB ↗www.oncokb.org/gene/PPM1D/L538*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=106572271
- 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= 6.19495e-07; MAF= 0.00006%, 1/1614218 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47435e-07; MAF= 0.00008%, 1/1180032 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
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 classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105190359, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.