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 ↗

Gene diagram · NM_003620.3 · variants mapped to exon structure

PPM1D NM_003620.3

Fetching transcript structure from UCSC…

Applied criteria · 1 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

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