Starting
Initialising…
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PMS2
Final classification
VUS
PMS2 c.1239del · p.Asp414ThrfsTer34
PMS2

The PMS2 NM_000535.7:c.1239del (p.(Asp414ThrfsTer34), p.(D414Tfs*34)) variant has been reported in ClinVar as Pathogenic by 6 clinical laboratories.

Gene
PMS2
Transcript
NM_000535.7
HGVS · transcript:coding
NM_000535.7:c.1239del
Consequence
N/A
GRCh38
chr7:5987525 CT>C
GRCh37
chr7:6027156 CT>C
Basis ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0.0 v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria. ▾
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0.0 v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PVS1PM2 VUS
PMS2 c.1239del

The PMS2 NM_000535.7:c.1239del (p.(Asp414ThrfsTer34), p.(D414Tfs*34)) variant has been reported in ClinVar as Pathogenic by 6 clinical laboratories.1 This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is present only once in gnomAD v4.1 (AF 6.19581e-07; 1/1613994 alleles), which is below the PMS2 PM2_Supporting threshold of 0.00002.2 This frameshift is predicted to introduce a premature termination codon after 34 altered amino acids, and the PMS2 VCEP specification applies PVS1 at very strong strength to frameshift variants with a premature stop at or before codon 798.3 SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.02); however, the primary predicted effect remains a truncating frameshift rather than an isolated splice or missense change.4

PVS1 + PM2 → VUS
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗cspec ↗
3 cspec ↗pvs1_gene_contextpvs1_variant_assessment
4 spliceai ↗cspec ↗
Gene diagram · NM_000535.7 · variants mapped to exon structure
PMS2 NM_000535.7
Fetching transcript structure from UCSC…
Applied criteria · 2 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 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      This variant is present in gnomAD v4.1 (AF= 6.19581e-07; MAF= 0.00006%, 1/1613994 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47482e-07; MAF= 0.00008%, 1/1179966 alleles, homozygotes = 0).
      v2.1
      Absent from gnomAD v2.1.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      6.2e-05% · 1 / 1,613,994
      0 hom
      European (non-Finnish)
      1 / 1,179,966
      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
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories). (ClinVarID = 1171824)
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      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; COSV56220545, n = 27 times).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      COSMIC ↗ Hotspots ↗
      Sources & reference links
      9Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 9 PMIDs not cited in assessment
      12697830 ↗ Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha. ONCOKB
      21376568 ↗ Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines. ONCOKB
      24362816 ↗ Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. ONCOKB
      10439048 ↗ Mice defective in the DNA mismatch gene PMS2 are hypersensitive to MNU induced thymic lymphoma and are partially protected by transgenic expression of human MGMT. ONCOKB
      10874005 ↗ Mutagenesis in PMS2- and MSH2-deficient mice indicates differential protection from transversions and frameshifts. ONCOKB
      16144131 ↗ Two PMS2 mutations in a Turcot syndrome family with small bowel cancers. ONCOKB
      20487569 ↗ MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. ONCOKB
      23619274 ↗ American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR