Classification rationale

PVS1PM2PP5 Pathogenic

MSH2 c.1147C>T

The MSH2 NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*) variant has been reported in ClinVar and includes an expert panel Pathogenic classification.¹ This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%), which is below the MSH2 PM2 threshold of 0.00002.² This nonsense variant introduces a premature stop at codon 383, which is well upstream of the MSH2 codon 891 cutoff for very strong PVS1 evidence and is consistent with loss of function as an established disease mechanism for MSH2-related disease.³

PVS1 + PM2 + PP5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_decisiontree_mmr

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 · 3 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 · 3

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

This variant is a nonsense change, NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*), in MSH2. Under the MSH2-specific ClinGen InSiGHT specification, nonsense variants introducing a premature termination codon at or before codon 891 meet PVS1 at very strong strength; this stop occurs at codon 383, well upstream of that threshold and is consistent with loss of function as an established disease mechanism.

MSH2-specific PVS1 rule for nonsense variants at or before codon 891Variant consequence p.Arg383Ter / p.R383*MSH2 loss of function is an established disease mechanism in the active VCEP framework

cspec ↗

PM2 supporting Pathogenic

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%) with no homozygotes. This frequency is below the MSH2 PM2 threshold of 0.00002 (1 in 50,000 alleles), supporting PM2.

Absent from gnomAD v2.1gnomAD v4.1 total AF 1.23911e-06MSH2 CSPEC PM2 threshold <0.00002

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PP5 supporting Pathogenic

Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.

Criterion marked not applicable by MSH2 CSPECClinVar expert panel classification

cspec ↗clinvar ↗

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

Pathogenic

PS2 No de novo data were identified for this variant, so PS2 cannot be assessed.

PS3 No variant-specific calibrated functional assay or RNA study demonstrating a damaging effect under the approved MMR assay framework was identified, so PS3 cannot be applied.

PM3 No biallelic observation or points-based recessive evidence was identified for this variant, so PM3 cannot be assessed.

PP1 No co-segregation data were identified for this variant, so PP1 cannot be assessed.

PP4 No tumor microsatellite instability result, mismatch repair immunohistochemistry result, or other phenotype data were identified to determine whether the clinical findings meet the MSH2-specific PP4 criteria.

Benign

BA1 This variant does not meet BA1 because the gnomAD v4.1 allele frequency is 1.23911e-06, which is far below the BA1 threshold of 0.001 (0.1%).

BS1 This variant does not meet BS1 because the gnomAD v4.1 allele frequency is 1.23911e-06, which is well below the BS1 threshold of 0.0001 (0.01%).

BS2 No confirmed in trans co-occurrence data with a pathogenic MSH2 variant in an individual without features of constitutional mismatch repair deficiency were identified, so BS2 cannot be assessed.

BS3 No variant-specific calibrated functional assay or RNA study demonstrating retained function or no mRNA abnormality was identified, so BS3 cannot be applied.

BS4 No segregation data were identified showing lack of co-segregation with disease, so BS4 cannot be assessed.

BP5 No tumor data were identified showing mismatch repair findings inconsistent with MSH2 involvement, so BP5 cannot be assessed.

N/A · 14 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23911e-06; MAF= 0.00012%, 2/1614058 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09823e-05; MAF= 0.00110%, 1/91056 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,614,058
0 hom

South Asian 1 / 91,056	0.0011%
European (non-Finnish) 1 / 1,180,020	8.5e-05%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

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 (20 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). 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 previously been reported in somatic cancers (COSMIC; COSV51878760, n = 9 times).

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

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