Classification rationale

PVS1PM2 VUS

MSH2 c.2034T>A

The MSH2 c.2034T>A (p.Tyr678Ter; p.Y678*) variant has been reported in ClinVar as pathogenic by 2 clinical laboratories.¹ 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 v4.² 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.³ 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.⁴

PVS1 + PM2 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗pvs1_variant_assessmentpvs1_gene_context

4 spliceai ↗cspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000251.3 · variants mapped to exon structure

MSH2 NM_000251.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 11 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong review Pathogenic

This variant is a nonsense change predicted to create p.(Tyr678Ter). Under the MSH2 VCEP specification, nonsense variants introducing a premature stop codon at or before codon 891 meet PVS1; this stop occurs at codon 678 and supports loss of function as the disease mechanism.

NM_000251.3:c.2034T>A predicts NP_000242.1:p.(Tyr678Ter)/p.(Y678*)MSH2 VCEP PVS1 rule: nonsense/frameshift variants with PTC <= codon 891 qualify for PVS1

cspec ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v4.1 and gnomAD v2.1. Absence from gnomAD v4.1 is below the MSH2 VCEP PM2 threshold of less than 0.00002 and supports PM2 at supporting strength.

Absent from gnomAD v4.1Absent from gnomAD v2.1MSH2 VCEP PM2 threshold: allele frequency <0.00002 in gnomAD v4

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

Assessed · not applied · 2 not met · 9 not assessed

Pathogenic

PS2 No de novo occurrence with confirmed parentage was identified for this variant.

PS3 No calibrated variant-specific functional assay or constitutional RNA study demonstrating a damaging effect was identified for this variant, so PS3 cannot be applied independently of PVS1.

PM3 No confirmed biallelic or in trans observation relevant to the MSH2 VCEP PM3 scoring system was identified for this variant.

PP1 No pedigree data were identified showing co-segregation of this variant with Lynch syndrome-related disease.

PP4 No tumor microsatellite instability result, mismatch repair immunohistochemistry pattern, or other phenotype data were identified to determine whether the MSH2 VCEP PP4 thresholds are met.

Benign

BA1 This variant is absent from gnomAD v4.1 and therefore does not reach the BA1 threshold of at least 0.001.

BS1 This variant is absent from gnomAD v4.1 and therefore does not reach the BS1 threshold of at least 0.0001.

BS2 No phase-confirmed observation of this variant in trans with a known pathogenic MSH2 variant in a person without clinical evidence of constitutional mismatch repair deficiency was identified.

BS3 No calibrated variant-specific functional assay or constitutional RNA study demonstrating a benign effect was identified for this variant, so BS3 cannot be applied.

BS4 No segregation study or Bayes likelihood ratio was identified showing lack of co-segregation with disease.

BP5 No tumor data were identified showing microsatellite stable tumors, intact mismatch repair protein expression, or an inconsistent mismatch repair loss pattern that would support BP5.

N/A · 15 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 579638)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.

SpliceAI ↗

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

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

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

10946232 ↗ Structure and function of mismatch repair proteins. ONCOKB

11257106 ↗ Deficient DNA mismatch repair: a common etiologic factor for colon cancer. ONCOKB

15528792 ↗ Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database. ONCOKB

23391514 ↗ Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities. ONCOKB

7726159 ↗ Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. ONCOKB

8566964 ↗ CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations. ONCOKB

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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