PPM1D c.1347_1348delinsG, p.Phe449LeufsTer2
NM_003620.3:c.1347_1348delinsG
Pathogenic
Pathogenic classification based on one Strong (PS3) and two Moderate (PM1, PM2) criteria supporting a damaging gain-of-function C-terminal truncation in PPM1D, consistent with ACMG guidelines.
ACMG/AMP Criteria Applied
PS3
PM1
PM2
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.1347_1348delinsG
Protein Change
F449Lfs*2
Location
Exon 6
(Exon 6 of 6)
5'Exon Structure (6 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 449 in gene PPM1D
Variant interpretation based on transcript NM_003620.4
Genome Browser
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HGVS InputNM_003620:c.1347_1348delinsG
Active Tracks
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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
No evidence of other pathogenic variants at position 449 in gene PPM1D
Functional Summary
Gain-of-Function
The PPM1D F449Lfs*2 variant is functionally characterized as a gain-of-function mutation. Truncating mutations in the C-terminal portion of PPM1D, including this variant, 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. Functional studies support the damaging effect of this variant.
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." The evidence for this variant shows: PPM1D F449Lfs*2 results in a C-terminal truncation that escapes nonsense-mediated decay and acts via gain-of-function rather than LoF. Therefore, this criterion is not applied because the disease mechanism is gain-of-function, not loss-of-function.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change." The evidence for this variant shows: No known pathogenic variant results in the same amino acid change F449Lfs*2. 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 de novo segregation data are available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: Functional studies demonstrate that F449Lfs*2 increases PPM1D protein stability, attenuates DNA damage response, enhances cell growth and colony formation, and drives leukemia development in vivo. Therefore, this criterion is applied at Strong strength because the variant has robust functional evidence of a damaging 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 cohort prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Moderate)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hotspot or well-established functional domain without benign variation." The evidence for this variant shows: F449Lfs*2 lies within the C-terminal hotspot region of PPM1D where truncating mutations drive gain-of-function cancer predisposition. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)." The evidence for this variant shows: Not observed in population databases (gnomAD MAF = 0%). 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: No trans or zygosity data are available, and PPM1D-associated disease is dominant. 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 or stop-loss variants." The evidence for this variant shows: This is a frameshift leading to early stop, not an in-frame change. 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 pathogenic missense change has been seen." The evidence for this variant shows: This is a frameshift variant, not a missense change. 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 de novo data are available. 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." The evidence for this variant shows: No segregation data are 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 a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: This is a frameshift 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/gene product." The evidence for this variant shows: In silico splicing analysis (SpliceAI score 0) and other computational predictions do not support an impact. 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 highly specific for a disease with a single genetic etiology." The evidence for this variant shows: No phenotype or family history data are 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 variant as pathogenic, but without accessible evidence." The evidence for this variant shows: No external reputable source classification is available. 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 too high for the disorder." The evidence for this variant shows: Absent from population databases. 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 the disorder." The evidence for this variant shows: Absent from population databases. 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 with full penetrance expected at an early age." The evidence for this variant shows: No data in healthy individuals. 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 function or splicing." The evidence for this variant shows: Functional studies show a damaging gain-of-function effect. 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." The evidence for this variant shows: No segregation data are available. 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 LoF causes disease." The evidence for this variant shows: This is a frameshift variant, 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 a pathogenic variant." The evidence for this variant shows: No data on cis/trans phase. 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 a repetitive region without known function." The evidence for this variant shows: This is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
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: Computational predictions are limited to splicing and are not relevant for a frameshift. Therefore, this criterion is not applied.
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 information is available. 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 without accessible evidence." The evidence for this variant shows: No benign classification from reputable sources. 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 impact on splicing." The evidence for this variant shows: This is a frameshift variant, not synonymous. Therefore, this criterion is not applied.