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LYFE SCIENCES
Project: HERA
NM_000535.7:c.1239del
p.Asp414ThrfsTer34  ·  PMS2
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Classification rationale
1

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

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗ gnomad_canada ↗ cspec ↗
3

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.

cspec ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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).
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories). (ClinVarID = 1171824)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
SpliceAI ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueD414
Hotspots ↗