About PPM1D
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPM1D c.1440del, p.(Ala481ProfsTer2)
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: 0
Pathogenic criteria applied · 1
PM2Met
PM2
This variant is very rare in population databases. In gnomAD v2.1 it is present at AF 3.98108e-06 (0.00040%, 1/251188 alleles), and in gnomAD v4.1 it is present at AF 6.19528e-07 (0.00006%, 1/1614132 alleles), both well below the 0.1% threshold used for PM2.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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.
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 / 1,614,132 alleles
gnomAD v4.1: 1 / 1,614,132 alleles. Recorded AF 6.19528e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98108e-06; MAF= 0.00040%, 1/251188 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81042e-06; MAF= 0.00088%, 1/113502 alleles, homozygotes = 0).
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: 1 met · 6 not met · 12 not assessed · 9 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 c.1440del (p.Ala481ProfsTer2, p.A481Pfs*2) variant has been observed in somatic cancers and has not been reported in ClinVar.
This variant is very rare in population databases, with an allele frequency of 3.98108e-06 in gnomAD v2.1 and 6.19528e-07 in gnomAD v4.1, which is below the 0.1% PM2 threshold.
Functional studies of truncating exon 6 PPM1D variants indicate increased protein stability and phosphatase activity, supporting an abnormal gain-of-function mechanism for this variant class rather than a simple loss-of-function effect.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.
No criteria match.
Met · 1
PM2 MetThis variant is very rare in population databases. In gnomAD v2.1 it is present at AF 3.98108e-06 (0.00040%, 1/251188 alleles), and in gnomAD v4.1 it is present at AF 6.19528e-07 (0.00006%, 1/1614132 alleles), both well below the 0.1% threshold used for PM2. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM2
Evidence considered
- gnomAD v2.1 AF 3.98108e-06
- gnomAD v4.1 AF 6.19528e-07
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 This variant is a frameshift in exon 6, the last exon of PPM1D, and is predicted to truncate the protein at p.Ala481ProfsTer2 rather than create a typical loss-of-function allele subject to nonsense-mediated decay. Available functional evidence indicates that truncating exon 6 PPM1D variants produce a stable, overactive protein, so the generic PVS1 loss-of-function criterion is not supported for this variant class. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 with ClinGen SVI PVS1 framework
Evidence considered
- Frameshift variant in exon 6/last exon
- Predicted protein consequence p.Ala481ProfsTer2 (p.A481Pfs*2)
- Published exon 6 truncating variants show gain-of-function behavior
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗oncokb ↗PMID:25742468 ↗PMID:29954749 ↗PMID:37709843 ↗
PS4 This variant has been observed in somatic cancers, but no germline case-control enrichment or statistically increased prevalence in affected individuals compared with controls was identified. Somatic observations alone do not meet PS4. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS4
Evidence considered
- Somatic cancer observation
- No ClinVar germline entry identified
Still missing
- Germline case-control or robust prevalence data
Sources
PM1 Published data indicate that pathogenic truncating PPM1D variants often cluster in exon 6, but this specific variant was not shown to lie in a statistically significant hotspot in Cancer Hotspots and no critical benign-variation-depleted domain threshold was established for applying PM1 here. Available evidence is therefore insufficient to meet PM1. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM1
Evidence considered
- Cancer Hotspots did not identify a statistically significant hotspot at A481
- Literature supports exon 6 clustering of truncating variants
Still missing
- Validated hotspot or critical-domain specification for germline PPM1D interpretation
Sources
BA1 The population frequency is far below the BA1 threshold of 1%. In gnomAD v4.1 the allele frequency is 6.19528e-07 (0.00006%), so BA1 is not met. Details ▾Hide ▴
Rule
Generic ACMG/AMP BA1
Evidence considered
- gnomAD v4.1 AF 6.19528e-07
- gnomAD v2.1 AF 3.98108e-06
Sources
BS1 The population frequency is far below the BS1 threshold of 0.3%. In gnomAD v4.1 the allele frequency is 6.19528e-07 (0.00006%), and in gnomAD v2.1 it is 3.98108e-06 (0.00040%), so BS1 is not met. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS1
Evidence considered
- gnomAD v4.1 AF 6.19528e-07
- gnomAD v2.1 AF 3.98108e-06
Sources
BS3 Available functional studies do not show a benign or normal effect for truncating exon 6 PPM1D variants. Instead, these studies support abnormal increased activity or stability, so BS3 is not met. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS3
Evidence considered
- Published exon 6 truncating variants show abnormal function
- OncoKB reports likely gain-of-function biology
Sources
Not assessed · 12 · no assessment recorded
PS2 No confirmed de novo occurrence with verified parentage was identified, so PS2 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS2
Still missing
- Documented parental testing and confirmed de novo status
PS3 Available studies show that truncating variants in exon 6 of PPM1D can increase protein stability and phosphatase activity, which is consistent with an abnormal functional effect for this variant class. However, no well-established functional study of this exact c.1440del variant in the relevant germline disease context was identified, so PS3 was not applied. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS3
Evidence considered
- OncoKB classifies the variant as Likely Oncogenic with likely gain-of-function biology
- Published truncating exon 6 variants show enhanced or abnormal PPM1D activity
Still missing
- Validated functional study of NM_003620.3:c.1440del specifically
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified, so PM6 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM6
Still missing
- Reported de novo occurrence data
PP1 No segregation data were identified for this variant, so PP1 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP1
Still missing
- Family segregation data
PP4 No phenotype or family-history data specific enough to assess a highly specific PPM1D-related clinical presentation were identified, so PP4 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP4
Still missing
- Detailed phenotype and family history
PP5 No pathogenic classification from a reputable source without available supporting evidence was identified. ClinVar does not contain this variant, so PP5 was not applied. Details ▾Hide ▴
BS2 The available population data show only a single allele in gnomAD and do not demonstrate observation in healthy adults at a frequency sufficient to support BS2. Therefore BS2 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS2
Evidence considered
- Single allele observed in gnomAD
Still missing
- Well-documented observations in unaffected adults
Sources
BS4 No segregation studies showing lack of segregation with disease were identified, so BS4 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP BS4
Still missing
- Family non-segregation data
BP2 No phase data with another pathogenic variant were identified, so BP2 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP2
Still missing
- Phase information with a second variant
BP3 No evidence was identified that this deletion lies in a repetitive region without a known function, so BP3 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP3
Still missing
- Repeat-region annotation showing a benign-prone context
BP5 No alternate molecular explanation for the phenotype was provided, so BP5 could not be assessed. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP5
Still missing
- Clinical report documenting an alternative genetic cause
BP6 No benign classification from a reputable source without available supporting evidence was identified. ClinVar does not contain this variant, so BP6 was not applied. Details ▾Hide ▴
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to a different nucleotide change that results in the same amino acid substitution. This variant is a frameshift deletion, so PS1 is not applicable. Details ▾Hide ▴
Rule
Generic ACMG/AMP PS1
Evidence considered
- Variant type is frameshift deletion
PM3 N/APM3 applies to recessive disorders with variants detected in trans. A recessive PPM1D disease mechanism and trans configuration data were not identified, so PM3 is not applicable. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM3
PM4 N/APM4 is intended for protein length changes such as in-frame indels or stop-loss variants that are not already addressed by a null-variant framework. This variant is a frameshift deletion, so PM4 is not the appropriate criterion. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM4
Evidence considered
- Variant type is frameshift deletion
PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is a frameshift deletion, so PM5 is not applicable. Details ▾Hide ▴
Rule
Generic ACMG/AMP PM5
Evidence considered
- Variant type is frameshift deletion
PP2 N/APP2 is used for missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is not missense, so PP2 is not applicable. Details ▾Hide ▴
Rule
Generic ACMG/AMP PP2
Evidence considered
- Variant type is frameshift deletion
PP3 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, but PP3 is not used here because this is a frameshift variant whose primary consequence is protein truncation rather than a predicted missense or splice-altering change. Details ▾Hide ▴
BP1 N/ABP1 applies to a missense variant in a gene where truncating variants are primarily pathogenic. This variant is not missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP1
Evidence considered
- Variant type is frameshift deletion
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BP4 is not used because this frameshift variant has an established protein-truncating consequence and splice prediction does not address the primary effect. Therefore BP4 is not applicable. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Evidence considered
- Variant type is frameshift deletion
Identifiers
- Gene
- PPM1D
- Transcript
- NM_003620.3
- Coding (HGVS c.)
- NM_003620.3:c.1440del
- Protein (HGVS p.)
- NP_003611.1:p.(Ala481ProfsTer2)
- GRCh38
- chr17:60663171 TA>T
- GRCh37
- chr17:58740532 TA>T
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 / 1,614,132 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 251,188 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,614,132 alleles · 0 hom
| European (non-Finnish)1 / 1,179,954 | 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.
gnomAD v2.1
AF 4e-06 · 1 / 251,188 alleles · 0 hom
| European (non-Finnish)1 / 113,502 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19528e-07; MAF= 0.00006%, 1/1614132 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47491e-07; MAF= 0.00008%, 1/1179954 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98108e-06; MAF= 0.00040%, 1/251188 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81042e-06; MAF= 0.00088%, 1/113502 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, but PP3 is not used here because this is a frameshift variant whose primary consequence is protein truncation rather than a predicted missense or splice-altering change. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BP4 is not used because this frameshift variant has an established protein-truncating consequence and splice prediction does not address the primary effect. Therefore BP4 is not applicable. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 is not applicable. Details ▾Hide ▴
Rule
Generic ACMG/AMP BP7
Evidence considered
- Variant type is frameshift deletion
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 / 1,614,132 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.1440delA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-58740532-TA-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-60663171-TA-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003620.3%3Ac.1440…
- OncoKB ↗www.oncokb.org/gene/PPM1D/A481Pfs*2
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=106568697
- 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= 6.19528e-07; MAF= 0.00006%, 1/1614132 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47491e-07; MAF= 0.00008%, 1/1179954 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98108e-06; MAF= 0.00040%, 1/251188 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81042e-06; MAF= 0.00088%, 1/113502 alleles, homozygotes = 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 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; COSV59957766, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.