NM_003620.3:c.1619del

PPM1D · NP_003611.1:p.(Glu540GlyfsTer7) · NM_003620.3

GRCh37: chr17:58740713 GA>G · GRCh38: chr17:60663352 GA>G

Gene: PPM1D Transcript: NM_003620.3

Final call

VUS

PVS1 strong PM2 supporting

Variant details

Gene

PPM1D

Transcript

NM_003620.3

Protein

NP_003611.1:p.(Glu540GlyfsTer7)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_003620.3:c.1619del (p.Glu540GlyfsTer7) is a frameshift deletion in exon 6 (terminal exon) of PPM1D, predicted to result in premature termination with removal of the C-terminal degradation domain.

This variant is absent from gnomAD v2.1 and v4.1 (0/1,614,172 alleles, AF=0.0%) across all ancestral populations, and absent from gnomAD-Canada v1.0.

The variant is absent from ClinVar and has no clinical germline classification. It has been observed as a somatic event in COSMIC (COSV99045424, n=2).

OncoKB curates this variant as Likely Oncogenic with predicted gain-of-function effect, consistent with the broader literature on PPM1D exon 6 truncating mutations.

Five publications were reviewed in full text; none specifically mention NM_003620.3:c.1619del (p.Glu540GlyfsTer7). PMID:24880341 reports a nonsense variant at the same codon (E540X) in brainstem gliomas in a somatic context.

SpliceAI predicts no splicing impact (max delta score 0.00). REVEL and BayesDel scores are not available for this indel variant.

Under the generic ACMG/AMP 2015 classification framework (PMID:25741868), PVS1_Strong and PM2_Supporting are assigned. This combination (1 Strong + 1 Supporting) does not meet the threshold for Likely Pathogenic (requires 1 Strong + 1-2 Moderate, 3 Moderate, or 2 Moderate + 2 Supporting). The overall classification is Variant of Uncertain Significance (VUS).

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	Met	NM_003620.3:c.1619del is a frameshift deletion in exon 6 (the terminal exon) of PPM1D, predicted to cause premature termination at p.Glu540GlyfsTer7, removing the C-terminal 66 amino acids including the degradation signal domain. Under ClinGen SVI PVS1 recommendations (PMC6185798), frameshift variants are eligible for PVS1 when loss of function is an established disease mechanism. PPM1D germline loss-of-function disease context is supported by literature review. However, the variant resides in the last exon and is predicted to escape nonsense-mediated decay; PPM1D exon 6 truncations have been characterized as gain-of-function in functional studies. Downgraded from PVS1_VeryStrong to PVS1_Strong per PMC6185798 due to NMD escape and residual protein expression with retained phosphatase domain, though the removed C-terminal region contains a functionally critical degradation signal.	pvs1_generic_framework gnomad_v4
PS1	N/A	PS1 requires the same amino acid change to result from a different nucleotide substitution. This variant is a single-nucleotide deletion causing a frameshift, not a missense substitution amenable to PS1 assessment.
PS2	Not met	No de novo confirmation data are available for this variant. No published trio or parentage testing studies report NM_003620.3:c.1619del as a confirmed de novo event.
PS3	Not met	No variant-specific functional studies of NM_003620.3:c.1619del (p.Glu540GlyfsTer7) were identified in the reviewed literature. While PPM1D exon 6 truncating mutations have been functionally characterized as gain-of-function in multiple publications, no study directly tested or reported on this exact variant in a functional assay.
PS4	Not met	No case-control studies or cohort reports documenting NM_003620.3:c.1619del in affected individuals were identified. The variant is absent from ClinVar and has been observed only in COSMIC as a somatic event (COSV99045424, n=2), which does not constitute germline case-level evidence for PS4.	clinvar
PS5	N/A	PS5 is not part of the generic ACMG/AMP 2015 classification framework. It was introduced in specific VCEP/CSPEC frameworks for particular genes and has no defined role in generic ACMG adjudication.
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot as determined by cancerhotspots.org analysis. While exon 6 of PPM1D is a recognized mutational cluster region for truncating mutations in the literature, the specific residue Glu540 does not meet the statistical hotspot threshold required for PM1 under the generic ACMG/AMP framework.
PM2	Met	NM_003620.3:c.1619del is absent from gnomAD v2.1 and v4.1 (0/1,614,172 alleles), with zero allele count across all ancestral populations. This meets the PM2 threshold for absence in population databases (allele frequency <0.1%) under the non-VCEP generic ACMG framework.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped per user instruction.
PM4	N/A	PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is an out-of-frame deletion resulting in a frameshift and premature termination, which is assessed under PVS1. Under ACMG/AMP 2015, PM4 should not be stacked with PVS1 for the same variant.
PM5	N/A	This is a frameshift variant, not a missense change. PM5 requires a different pathogenic missense variant at the same amino acid residue as the variant being assessed. No same-residue missense comparator could be identified for this frameshift; the PM5 candidate search was unable to confirm classic same-residue semantics.
PM6	Not met	No de novo data are available for this variant. No published studies report NM_003620.3:c.1619del as a confirmed de novo event with confirmed maternity and paternity.
PP1	Not met	No segregation data are available for this variant. No published family studies report cosegregation of NM_003620.3:c.1619del with disease in affected family members.
PP2	N/A	PP2 applies to missense variants in genes where missense variation is a known disease mechanism and the gene has a low rate of benign missense variation. This is a frameshift variant, not a missense variant.
PP3	Not met	In silico pathogenicity prediction tools (REVEL, BayesDel) are not applicable to indel variants and returned no scores. SpliceAI predicts no splicing impact (max delta score = 0.00). No multiple lines of computational evidence support a deleterious effect for this variant.	spliceai
PP4	Not met	No specific patient phenotype data are available for individuals harboring NM_003620.3:c.1619del as a germline variant. The variant has been observed in COSMIC as a somatic event (n=2) but this does not provide germline phenotype specificity.
PP5	N/A	PP5 requires a reputable clinical diagnostic source to have classified the variant as pathogenic. The variant is absent from ClinVar and no clinical diagnostic laboratory classification is available. OncoKB annotation ('Likely Oncogenic') is a somatic/oncogenicity resource and does not constitute a germline clinical classification suitable for PP5.
BA1	Not met	NM_003620.3:c.1619del is absent from gnomAD v4.1 (0/1,614,172 alleles, AF=0.0%). The allele frequency is well below the BA1 threshold of >1% in any population under the generic ACMG/AMP framework.	gnomad_v4
BS1	Not met	NM_003620.3:c.1619del is absent from gnomAD v4.1 (0/1,614,172 alleles, AF=0.0%). The allele frequency is well below the BS1 threshold of >0.3% in any population under the generic ACMG/AMP framework.	gnomad_v4
BS2	Not met	BS2 requires observation of the variant in homozygous state or in trans with a pathogenic variant in healthy individuals. The variant is absent from gnomAD, providing no homozygous count data. Insufficient evidence to assess BS2.
BS3	Not met	No variant-specific functional studies demonstrate a benign or neutral effect for NM_003620.3:c.1619del. The broader literature on PPM1D exon 6 truncations indicates gain-of-function effects (enhanced phosphatase activity, chemoresistance), which are deleterious rather than benign. No evidence supports a benign functional impact.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease. BS4 requires observation of the variant in unaffected family members of multiple affected families.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary mechanism of disease. This variant is itself a frameshift (truncating) variant.
BP2	Not met	BP2 requires observation of the variant in trans with a known pathogenic dominant variant, or in cis with a pathogenic variant. No such observations are available for NM_003620.3:c.1619del.
BP3	Not met	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This variant is a frameshift deletion in exon 6, not an in-frame event in a repetitive region.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI predicts no splice effect (max delta 0.00), but this is a protein-truncating frameshift variant where splice prediction is not the primary computational evidence needed. REVEL and BayesDel are not applicable to indels. The single line of evidence (SpliceAI) is insufficient to meet BP4.	spliceai
BP5	Not met	BP5 requires observation of the variant in a case with an alternate molecular basis for disease. No such data are available for NM_003620.3:c.1619del.
BP6	N/A	BP6 requires a reputable clinical diagnostic source to have classified the variant as benign. NM_003620.3:c.1619del is absent from ClinVar and has no clinical diagnostic laboratory classification available.
BP7	N/A	BP7 applies to synonymous variants predicted to have no impact on splicing. This is a frameshift deletion variant with a clear predicted impact on protein sequence.

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