PPM1D c.1619del, p.(Glu540GlyfsTer7)

29 criteria with recorded statuses: 2 met · 17 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per user instruction. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThis 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. Details ▾Hide ▴

Evidence considered

• PM5 candidate search: no same-residue pathogenic missense comparators identified

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

PP5 N/APP5 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. Details ▾Hide ▴

Evidence considered

• Variant absent from ClinVar
• OncoKB 'Likely Oncogenic' is a somatic annotation
• not a germline clinical classification

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary mechanism of disease. This variant is itself a frameshift (truncating) variant. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ABP6 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. Details ▾Hide ▴

Evidence considered

• Variant absent from ClinVar

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene

PPM1D

Transcript

NM_003620.3

Coding (HGVS c.)

NM_003620.3:c.1619del

Protein (HGVS p.)

NP_003611.1:p.(Glu540GlyfsTer7)

GRCh38

chr17:60663352 GA>G

GRCh37

chr17:58740713 GA>G

COSMIC

COSV99045424

Gene diagram

Every interpreted variant in PPM1D, mapped onto the exon structure of NM_003620.3. Select a row to find it on the plot.

By genetic ancestry

Statements

SpliceAI and Pangolin

Other predictors

REVEL

Not available

BayesDel

Not available

How the predictions were used

PP3 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. Details ▾Hide ▴

Evidence considered

• SpliceAI: max delta 0.00 — no splice impact predicted
• REVEL: not applicable (indel)
• BayesDel: not applicable (indel)
• HCI prior: gene not supported

Still missing

• No in silico missense prediction tools applicable to frameshift variants

Sources

spliceai ↗

BP4 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. Details ▾Hide ▴

Evidence considered

• SpliceAI: max delta 0.00
• no splice impact predicted
• REVEL/BayesDel: not applicable to indels

Still missing

• No computational tools suitable for assessing pathogenicity of frameshift variants at the protein level

Sources

spliceai ↗

BP7 N/ABP7 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. Details ▾Hide ▴

No further detail was recorded.

Statement

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

• Genetic variants and mutations of PPM1D control the response to DNA damage.

  Characterizes PPM1D (Wip1) genetic variants and cancer mutations. Reports missense SNPs L120F, P322Q, and I496V with dominant-negative effects, and truncating hotspot mutations at E525X and R552X in primary human cancers. Demonstrates both gain- and loss-of-function PPM1D mutations in cancer.

  Does not name this variant
  PMID 23907125 ↗
• Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

  Identifies somatic PPM1D truncating mutations in exon 6 in 37.5% of H3F3A K27M-mutated brainstem gliomas. Reports nonsense mutations at Glu472, Leu484, Ser516, Glu525, and Glu540 (E540X), and a frameshift at Asn448. Functional studies confirm gain-of-function suppression of DNA damage response. The specific variant NM_003620.3:c.1619del (p.Glu540GlyfsTer7) is a different variant (frameshift) at the same codon as the reported E540X (nonsense) mutation.

  Does not name this variant
  PMID 24880341 ↗
  Quoted passage

  Six of the PPM1D mutations were nonsense mutations targeting Glu472, Leu484, Ser516, Glu525 (2 cases), and Glu540, while one was a frameshift mutation that disrupted Asn448 and resulted in a de novo stop codon

  Results; describes PPM1D nonsense mutations including E540X

• Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients.

  Screens blood DNA from 543 non-small-cell lung cancer patients for PPM1D exon 6 truncating mutations. Identifies five frameshift mutations (four 1-bp deletions, one 2-bp deletion) in 0.92% of patients, all in squamous cell carcinoma. Demonstrates R458X gain-of-function with enhanced p53 Ser15 dephosphorylation. None of the reported mutations correspond to NM_003620.3:c.1619del.

  Does not name this variant
  PMID 25742468 ↗
  Quoted passage

  In five patients (0.92%), we detected the electropherogram pattern consistent with the deletion/insertion mutations.

• PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells.

  Demonstrates that PPM1D truncating mutations in exon 6 confer chemotherapy resistance and selective expansion of hematopoietic cells in vitro and in vivo. Uses CRISPR-Cas9 to introduce frameshift mutations in PPM1D exon 6, showing gain-of-function through loss of a C-terminal degradation domain leading to protein overexpression. Functional rescue with allosteric PPM1D inhibitor GSK2830371.

  Does not name this variant
  PMID 29954749 ↗
  Quoted passage

  Truncating mutations in the terminal exon of PPM1D have been identified in clonal hematopoiesis and myeloid neoplasms, with a striking enrichment in patients previously exposed to chemotherapy.

• Classification and Personalized Prognosis in Myeloproliferative Neoplasms.

  Genomic characterization study of 2,035 myeloproliferative neoplasm patients. Reports PPM1D terminal exon truncating mutations in 1.5% of patients (45 mutations in 38 patients), making PPM1D the 8th most commonly mutated gene in this cohort. PPM1D mutations occurred both at diagnosis and emerged during treatment. No specific PPM1D variants are listed by HGVS nomenclature.

  Does not name this variant
  PMID 30304655 ↗
  Quoted passage

  We identified 45 truncating mutations in the terminal exon of PPM1D in 38 patients (1.5%), making PPM1D the 8th most commonly mutated gene in MPNs.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

All source links

• ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_003620.3%3Ac.1619del
• gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-58740713-GA-G?dataset=gnom…
• gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-60663352-GA-G?dataset=g…
• gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-60663352-GA-G
• SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_003620.3%3Ac.1619…
• OncoKB ↗www.oncokb.org/gene/PPM1D/E540Gfs*7
• COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=127457312
• Cancer hotspots ↗www.cancerhotspots.org/

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.