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.1 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.2 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).3 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.4
Final classification
Likely Pathogenic
PVS1PM2
PPM1D
c.1613del
p.Leu538Ter
This variant
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback.
Classification rationale
PVS1PM2
Likely Pathogenic
PPM1D c.1613del
PVS1 + PM2
→
Likely Pathogenic
4
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
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.
Gene diagram
· NM_003620.3 · variants mapped to exon structure
PPM1D
NM_003620.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
strong
review
Pathogenic
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.
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.
PM2
supporting
Pathogenic
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.
gnomAD v2.1: absent.gnomAD v4.1: 1 alleleAF 6.19495e-07
Assessed · not applied
· 4 not met · 15 not assessed
Pathogenic
PS1
No evidence was identified showing a different nucleotide change already established as pathogenic for the same protein consequence.
PS2
No confirmed de novo data with parental testing were identified.
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.
PS4
No case-control or statistically enriched germline case series were identified for this specific variant.
PM1
Available hotspot review did not identify this variant in a statistically significant hotspot, so current evidence does not support PM1.
PM3
No data were identified showing this variant in trans with another pathogenic variant in a recessive disease context.
PM6
No assumed de novo occurrence without full parental confirmation was identified.
PP1
No segregation data were identified.
PP4
No phenotype information was provided that would allow assessment of a highly specific PPM1D-related clinical presentation.
PP5
No reputable pathogenic classification from an external clinical database was identified because this variant is absent from ClinVar.
Benign
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.
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.
BS2
No evidence was identified showing this variant in healthy adult individuals at a frequency expected to argue against pathogenicity.
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.
BS4
No data were identified showing lack of segregation with disease in a family.
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.
BP3
No evidence was identified showing that this variant lies in a repetitive region without known function.
BP5
No alternate molecular explanation was provided that would account for the phenotype independently of this variant.
BP6
No reputable benign classification from an external clinical database was identified because this variant is absent from ClinVar.
N/A · 7
PM4 · PM5 · PP2 · PP3 · BP1 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
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).
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,614,218
0 hom
0 hom
European (non-Finnish) 1 / 1,180,032 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105190359, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links