Classification rationale

PM2PP3 VUS

MSH2 c.793-11_794dup

The MSH2 c.793-11_794dup (NP_000242.1:p.?) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1; in gnomAD v4.1 the observed allele frequency is 0, which is below the MSH2 PM2_Supporting threshold of less than 0.00002.² SpliceAI predicts a splice effect with a maximum delta score of 0.71, which is above the MSH2 PP3 threshold of 0.2 for non-canonical splice variants and above the BP4 no-impact threshold of 0.1.³

PM2 + PP3 → VUS

1 evidence.json.results.cosmicevidence.json.results.clinvar

2 evidence.json.results.gnomad.GNOMAD_V2_1evidence.json.results.gnomad.GNOMAD_V4_1MSH2/criteria.json:PM2

3 evidence.json.results.spliceaiMSH2/criteria.json:PP3MSH2/criteria.json:BP4

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 · 15 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

PM2 Supporting Pathogenic

This variant is absent from gnomAD v4.1, which is below the MSH2 PM2_Supporting threshold of less than 0.00002 (less than 1 in 50,000 alleles).

gnomAD v4.1: absentgnomAD v2.1: absentPM2_Supporting threshold: AF < 0.00002

PP3 Supporting Pathogenic

SpliceAI predicts a splice defect with a maximum delta score of 0.71, which is above the MSH2 PP3 threshold of 0.2 for non-canonical splice nucleotides and supports a predicted splicing impact.

SpliceAI DS_AG: 0.71SpliceAI max delta score: 0.71PP3 threshold for non-canonical splice variants: >=0.2

Assessed · not applied · 6 not met · 9 not assessed

Pathogenic

PP4 No colorectal or endometrial tumor MSI result, tumor genome result, or mismatch repair immunohistochemistry result was identified, so the MSH2-specific PP4 tumor criteria cannot be evaluated.

PS1 PS1 for non-canonical splice variants requires a previously established pathogenic or likely pathogenic variant affecting the same splice nucleotide with similar or worse splicing prediction.

PS2 No de novo data, parental confirmation, or tumor evidence consistent with MSH2 deficiency were identified, so PS2 cannot be assessed.

PP1 No family segregation data or Bayes likelihood ratio were identified, so co-segregation with disease cannot be assessed.

PVS1 This variant is a non-canonical intronic duplication at c.793-11_794dup and is not a canonical +/-1,2 splice variant, nonsense variant, frameshift variant, or exon-level duplication.

PS3 No variant-specific calibrated functional assay, constitutional RNA assay showing a damaging splice defect, or monoallelic expression data were identified, so PS3 cannot be applied.

PM3 No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic MSH2 variant in an individual with clinical features consistent with constitutional mismatch repair deficiency, so PM3 cannot be assessed.

Benign

BP7 This intronic duplication is located at c.793-11_794dup, which is 11 nucleotides upstream of the exon boundary.

BS4 No segregation studies or Bayes likelihood ratio data were identified, so lack of segregation with disease cannot be assessed.

BS3 No RNA study showing no splicing abnormality and no calibrated functional assay showing benign function were identified, so BS3 cannot be applied.

BP4 For intronic variants, BP4 requires SpliceAI to predict no splicing impact with a delta score of 0.1 or less.

BS1 BS1 requires a gnomAD v4 group maximum filtering allele frequency of at least 0.0001 and less than 0.001.

BP5 No tumor profile inconsistent with MSH2-associated disease and no alternate molecular explanation for the phenotype were identified, so BP5 cannot be assessed.

BA1 BA1 requires a gnomAD v4 group maximum filtering allele frequency of at least 0.001.

BS2 No evidence was identified showing this variant in trans with a known pathogenic MSH2 variant in an individual whose clinical features argue against constitutional mismatch repair deficiency, so BS2 cannot be assessed.

N/A · 11 BP3 · PM5 · BP2 · BP6 · PM1 · PP5 · PM6 · PS4 · PM4 · BP1 · PP2

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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.71).

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 ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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