Classification rationale

PM2 VUS

PPM1D c.1440del

The PPM1D c.1440del (p.Ala481ProfsTer2, p.A481Pfs*2) variant has been observed in somatic cancers and has not been reported in ClinVar.¹ This variant is very rare in population databases, with an allele frequency of 3.98108e-06 in gnomAD v2.1 and 6.19528e-07 in gnomAD v4.1, which is below the 0.1% PM2 threshold.² Functional studies of truncating exon 6 PPM1D variants indicate increased protein stability and phosphatase activity, supporting an abnormal gain-of-function mechanism for this variant class rather than a simple loss-of-function effect.³ SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.⁴

PM2 → VUS

1 oncokb ↗clinvar ↗PMID:25742468 ↗PMID:29954749 ↗PMID:37709843 ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗PMID:23907125 ↗PMID:25742468 ↗PMID:29954749 ↗PMID:37709843 ↗

4 spliceai ↗

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 · 1 applied · 18 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 · 1

Strength Supporting Moderate Strong Very strong

PM2 Pathogenic

This variant is very rare in population databases. In gnomAD v2.1 it is present at AF 3.98108e-06 (0.00040%, 1/251188 alleles), and in gnomAD v4.1 it is present at AF 6.19528e-07 (0.00006%, 1/1614132 alleles), both well below the 0.1% threshold used for PM2.

gnomAD v2.1 AF 3.98108e-06gnomAD v4.1 AF 6.19528e-07

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 6 not met · 12 not assessed

Pathogenic

PVS1 This variant is a frameshift in exon 6, the last exon of PPM1D, and is predicted to truncate the protein at p.Ala481ProfsTer2 rather than create a typical loss-of-function allele subject to nonsense-mediated decay.

PS2 No confirmed de novo occurrence with verified parentage was identified, so PS2 could not be assessed.

PS3 Available studies show that truncating variants in exon 6 of PPM1D can increase protein stability and phosphatase activity, which is consistent with an abnormal functional effect for this variant class.

PS4 This variant has been observed in somatic cancers, but no germline case-control enrichment or statistically increased prevalence in affected individuals compared with controls was identified.

PM1 Published data indicate that pathogenic truncating PPM1D variants often cluster in exon 6, but this specific variant was not shown to lie in a statistically significant hotspot in Cancer Hotspots and no critical benign-variation-depleted domain threshold was established for applying PM1 here.

PM6 No assumed de novo occurrence without full parental confirmation was identified, so PM6 could not be assessed.

PP1 No segregation data were identified for this variant, so PP1 could not be assessed.

PP4 No phenotype or family-history data specific enough to assess a highly specific PPM1D-related clinical presentation were identified, so PP4 could not be assessed.

PP5 No pathogenic classification from a reputable source without available supporting evidence was identified.

Benign

BA1 The population frequency is far below the BA1 threshold of 1%.

BS1 The population frequency is far below the BS1 threshold of 0.3%.

BS2 The available population data show only a single allele in gnomAD and do not demonstrate observation in healthy adults at a frequency sufficient to support BS2.

BS3 Available functional studies do not show a benign or normal effect for truncating exon 6 PPM1D variants.

BS4 No segregation studies showing lack of segregation with disease were identified, so BS4 could not be assessed.

BP2 No phase data with another pathogenic variant were identified, so BP2 could not be assessed.

BP3 No evidence was identified that this deletion lies in a repetitive region without a known function, so BP3 could not be assessed.

BP5 No alternate molecular explanation for the phenotype was provided, so BP5 could not be assessed.

BP6 No benign classification from a reputable source without available supporting evidence was identified.

N/A · 9 PS1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP4 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19528e-07; MAF= 0.00006%, 1/1614132 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47491e-07; MAF= 0.00008%, 1/1179954 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 3.98108e-06; MAF= 0.00040%, 1/251188 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81042e-06; MAF= 0.00088%, 1/113502 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,132
0 hom

European (non-Finnish)

1 / 1,179,954

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

0.0004% · 1 / 251,188
0 hom

European (non-Finnish)

1 / 113,502

0.00088%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.

OncoKB ↗

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; COSV59957766, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Check your email

Reset your password

Enter an access code

Your allowance