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LYFE SCIENCES
Project: HERA
NM_000251.3:c.2034T>A
p.Tyr678Ter  ·  MSH2
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Classification rationale
1

The MSH2 c.2034T>A (p.Tyr678Ter; p.Y678*) variant has been reported in ClinVar as pathogenic by 2 clinical laboratories.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the MSH2 VCEP PM2 threshold of less than 0.00002 in gnomAD v4.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

This nonsense variant introduces a premature stop codon at Tyr678; under the MSH2 VCEP specification, nonsense variants at or before codon 891 meet PVS1, and p.(Tyr678Ter) falls within that range.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is consistent with premature protein truncation rather than a predicted splice defect.

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
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 579638)
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 = 0.01). BayesDel score = 0.66.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueY678
Hotspots ↗