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LYFE SCIENCES
Project: HERA
NM_003620.3:c.1613del
p.Leu538Ter  ·  PPM1D
ACMG/AMP
Starting
Initialising…
0%
Legacy Engine
Processing…
Classification rationale
1

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.

oncokb ↗ clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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).

PMID:23907125 ↗ PMID:25742468 ↗ PMID:29954749 ↗ PMID:37709843 ↗
4

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.

pvs1_generic_framework ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueL538
Hotspots ↗