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
PPM1D
Final classification
Likely Pathogenic
PPM1D c.1613del · p.Leu538Ter
PPM1D
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 ↗
Gene diagram
· NM_003620.3 · variants mapped to exon structure
PPM1D
NM_003620.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
PMID pvs1_generic_framework
Found
Structured finding pending for this record — see source link.
Applied to
→PVS1 supports · met
Sources & reference links