Final classification

Pathogenic

PVS1PM2PP5

MSH2

c.1661+1G>A

p.?

This variant

Transcript

NM_000251.3

HGVS · transcript:coding

NM_000251.3:c.1661+1G>A

GRCh38

chr2:47466809 G>A

GRCh37

chr2:47693948 G>A

Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; maps to Pathogenic.

Classification rationale

PVS1PM2PP5 Pathogenic

MSH2 c.1661+1G>A

The MSH2 NM_000251.3:c.1661+1G>A (NP_000242.1:p.?) variant has been reported in ClinVar, including an InSiGHT expert panel classification of likely pathogenic and additional pathogenic/likely pathogenic clinical laboratory submissions.¹ This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,612,780 alleles; AF 6.20e-07), which is below the MSH2 VCEP PM2 threshold of 0.00002.² SpliceAI predicts a strong splice effect for this canonical donor variant (max delta score 0.97), supporting predicted disruption of normal splicing; however, this computational evidence was not counted separately because the same splice effect is captured under PVS1 for a canonical +1 splice-site variant.³

PVS1 + PM2 + PP5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗pvs1_variant_assessment

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 · 12 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 review Pathogenic

This variant affects the canonical +1 donor splice nucleotide in MSH2. Under the MSH2 InSiGHT specification, canonical ±1,2 splice variants can meet PVS1 at very strong strength when loss of function is an established disease mechanism and the predicted splice consequence is expected to create a null transcript; the available MSH2 PVS1 assessments support full-strength application for this variant. PP3 was not added because the same predicted splice effect should not be double-counted.

Canonical +1 splice donor variantMSH2 loss of function is an established disease mechanism in the applied VCEP frameworkVariant-level PVS1 scaffold suggests full-strength PVS1

cspec ↗

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,612,780 alleles; AF 6.20e-07, 0 homozygotes), which is below the MSH2 VCEP PM2 threshold of 0.00002 (1 in 50,000 alleles). This supports PM2 at supporting strength.

gnomAD v2.1 absentgnomAD v4.1 total AF 6.20e-07

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP5 supporting review Pathogenic

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

Criterion marked not applicable by VCEPClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 3 not met · 9 not assessed

Pathogenic

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

PS3 No validated variant-specific functional or RNA assay result was confirmed for this exact variant from the available evidence.

PM3 No evidence was identified that this variant occurred in trans with a pathogenic MSH2 variant in a case informative for CMMRD scoring.

PP1 No segregation data were identified to calculate a Bayes likelihood ratio for co-segregation with disease.

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

Benign

BA1 The population frequency does not reach the benign stand-alone threshold.

BS1 The population frequency does not reach the benign strong threshold.

BS2 No confirmed observation in trans with a known pathogenic MSH2 variant in a person whose clinical features argue against CMMRD was identified.

BS3 No well-established study showing normal splicing or preserved MSH2 function for this exact variant was confirmed.

BS4 No non-segregation data were identified to calculate a Bayes likelihood ratio arguing against pathogenicity.

BP4 Available computational evidence does not support no splice impact.

BP5 No tumor findings were identified that are inconsistent with MSH2-related mismatch repair deficiency.

N/A · 13 PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · BP1 · BP2 · BP3 · 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= 6.20047e-07; MAF= 0.00006%, 1/1612780 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.48089e-07; MAF= 0.00008%, 1/1179122 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,612,780
0 hom

European (non-Finnish)

1 / 1,179,122

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 v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel).

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.97). BayesDel score = 0.66.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

ACG clinical guideline: Genetic testing and management of hereditary gastrointes

PMID 25645574 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→PVS1 very strong

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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