Variant classification summary

NM_003620.3:c.1440delA

PPM1D · NP_003611.1:p.(Ala481ProfsTer2) · NM_003620.3

GRCh37: chr17:58740532 TA>T · GRCh38: chr17:60663171 TA>T

Gene: PPM1D Transcript: NM_003620.3

Final call

VUS

PM2

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.(Ala481ProfsTer2)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PPM1D c.1440del (p.Ala481ProfsTer2, p.A481Pfs*2) variant has been observed in somatic cancers and has not been reported in ClinVar.

2

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.

3

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.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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. Available functional evidence indicates that truncating exon 6 PPM1D variants produce a stable, overactive protein, so the generic PVS1 loss-of-function criterion is not supported for this variant class.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework oncokb PMID:25742468 PMID:29954749 PMID:37709843
PS1	N/A	PS1 applies to a different nucleotide change that results in the same amino acid substitution. This variant is a frameshift deletion, so PS1 is not applicable.
PS2	Not assessed	No confirmed de novo occurrence with verified parentage was identified, so PS2 could not be assessed.
PS3	Not assessed	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. However, no well-established functional study of this exact c.1440del variant in the relevant germline disease context was identified, so PS3 was not applied.	oncokb PMID:23907125 PMID:25742468 PMID:29954749 PMID:37709843
PS4	Not met	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. Somatic observations alone do not meet PS4.	oncokb clinvar PMID:25742468 PMID:29954749 PMID:37709843
PM1	Not met	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. Available evidence is therefore insufficient to meet PM1.	hotspots oncokb PMID:23907125 PMID:24880341 PMID:25742468 PMID:29954749 PMID:37709843
PM2	Met	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 gnomad_v4
PM3	N/A	PM3 applies to recessive disorders with variants detected in trans. A recessive PPM1D disease mechanism and trans configuration data were not identified, so PM3 is not applicable.
PM4	N/A	PM4 is intended for protein length changes such as in-frame indels or stop-loss variants that are not already addressed by a null-variant framework. This variant is a frameshift deletion, so PM4 is not the appropriate criterion.
PM5	N/A	PM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change has been established. This variant is a frameshift deletion, so PM5 is not applicable.
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified, so PM6 could not be assessed.
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be assessed.
PP2	N/A	PP2 is used for missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is not missense, so PP2 is not applicable.
PP3	N/A	SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, but PP3 is not used here because this is a frameshift variant whose primary consequence is protein truncation rather than a predicted missense or splice-altering change.	spliceai
PP4	Not assessed	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	Not assessed	No pathogenic classification from a reputable source without available supporting evidence was identified. ClinVar does not contain this variant, so PP5 was not applied.	clinvar
BA1	Not met	The population frequency is far below the BA1 threshold of 1%. In gnomAD v4.1 the allele frequency is 6.19528e-07 (0.00006%), so BA1 is not met.	gnomad_v4 gnomad_v2
BS1	Not met	The population frequency is far below the BS1 threshold of 0.3%. In gnomAD v4.1 the allele frequency is 6.19528e-07 (0.00006%), and in gnomAD v2.1 it is 3.98108e-06 (0.00040%), so BS1 is not met.	gnomad_v4 gnomad_v2
BS2	Not assessed	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. Therefore BS2 could not be assessed.	gnomad_v2 gnomad_v4
BS3	Not met	Available functional studies do not show a benign or normal effect for truncating exon 6 PPM1D variants. Instead, these studies support abnormal increased activity or stability, so BS3 is not met.	oncokb PMID:23907125 PMID:25742468 PMID:29954749 PMID:37709843
BS4	Not assessed	No segregation studies showing lack of segregation with disease were identified, so BS4 could not be assessed.
BP1	N/A	BP1 applies to a missense variant in a gene where truncating variants are primarily pathogenic. This variant is not missense, so BP1 is not applicable.
BP2	Not assessed	No phase data with another pathogenic variant were identified, so BP2 could not be assessed.
BP3	Not assessed	No evidence was identified that this deletion lies in a repetitive region without a known function, so BP3 could not be assessed.
BP4	N/A	SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but BP4 is not used because this frameshift variant has an established protein-truncating consequence and splice prediction does not address the primary effect. Therefore BP4 is not applicable.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was provided, so BP5 could not be assessed.
BP6	Not assessed	No benign classification from a reputable source without available supporting evidence was identified. ClinVar does not contain this variant, so BP6 was not applied.	clinvar
BP7	N/A	BP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 is not applicable.

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