PPM1D c.1613del, p.Leu538Ter
NM_003620.3:c.1613del
COSMIC ID: COSM9522669
Pathogenic
Functional studies (PS3) and absence from controls (PM2) support pathogenicity while computational evidence (BP4) supports benign. Combining one Strong and one Moderate ACMG criterion yields a Likely Pathogenic classification for this gain-of-function truncating variant in PPM1D.
ACMG/AMP Criteria Applied
PS3
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
PPM1D
Transcript
NM_003620.4
MANE Select
Total Exons
6
Strand
Forward (+)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_003620.2 | Alternative | 6 exons | Forward |
| NM_003620.3 | RefSeq Select | 6 exons | Forward |
Variant Details
HGVS Notation
NM_003620.3:c.1613del
Protein Change
L538*
Location
Exon 6
(Exon 6 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM9522669
Variant interpretation based on transcript NM_003620.4
Genome Browser
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HGVS InputNM_003620:c.1613del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Functional Summary
Gain-of-Function
The PPM1D L538* variant has been functionally characterized as a gain-of-function mutation. Truncating mutations in the C-terminal portion of PPM1D, including L538*, lead to increased protein stability and attenuate the activation of DNA damage response mediators such as p53 and H2AX. These mutations enhance cell growth and colony formation, confer resistance to chemotherapeutic agents, and are associated with increased development of acute myeloid leukemia in vivo.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion)." The evidence for this variant shows: c.1613delT is a truncating variant in PPM1D, but the pathogenic mechanism for PPM1D is gain-of-function rather than loss-of-function. Therefore, this criterion is not applied because loss-of-function is not a known disease mechanism for PPM1D.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: it is a frameshift leading to a stop codon, not a missense change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no information on de novo status or parental confirmation. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: in vitro and in vivo studies demonstrate that L538* truncations in PPM1D increase protein stability, attenuate DNA damage response, enhance cell growth, and confer chemoresistance. Therefore, this criterion is applied at Strong strength because multiple well-established functional studies support a damaging (gain-of-function) effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls." The evidence for this variant shows: no case-control or prevalence data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: no specific hot spot or domain annotation provided. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in population databases." The evidence for this variant shows: MAF = 0% in gnomAD and other control datasets. Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: PPM1D-related disease is not recessive and no trans data provided. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: c.1613delT is a frameshift leading to a premature stop, not an in-frame change or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: it is a truncating variant, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no data on de novo occurrence or parental testing. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease." The evidence for this variant shows: no family segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: it is a truncating variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: SpliceAI max score of 0 and no pathogenic in silico predictions. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype or clinical data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports as pathogenic but evidence not available." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is greater than expected for disorder (stand-alone benign)." The evidence for this variant shows: frequency = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder (strong benign)." The evidence for this variant shows: frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in healthy individuals for a fully penetrant dominant gene (strong benign)." The evidence for this variant shows: no healthy individual observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein or splicing." The evidence for this variant shows: functional studies demonstrate damaging/gain-of-function effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members (strong benign)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only loss-of-function causes disease." The evidence for this variant shows: it is truncating, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with another pathogenic variant (benign support)." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive region without known function." The evidence for this variant shows: it is a frameshift deletion leading to stop. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: SpliceAI max score of 0 and no deleterious in silico predictions. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no such case data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign but evidence not available." The evidence for this variant shows: not reported as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splicing impact." The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.