MSH2c.793-11_794dupUncertain significance

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Variant interpretation report

MSH2 c.793-11_794dup, p.?

NM_000251.3:c.793-11_794dup NP_000242.1:p.? View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MSH2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 2 supporting (pathogenic)
Expert rules: ClinGen MSH2 VCEP v2.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): 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).
PP3 (supporting): 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.

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.

01The reasoning

How it was classified

The recorded framework is ClinGen MSH2 VCEP v2.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PM2Supporting

PM2 · supporting

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).

PP3Supporting

PP3 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

Official InSiGHT Hereditary Colorectal Cancer/Polyposis CSPEC final-classification framework (criteria-combination rules derived from Richards et al. 2015 and retrieved in final_classification_framework.json) was applied to the adjudicated criteria.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

No screenshot for this evidence

Computational predictions

Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · PP3 →

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

Not assessed

No COSMIC evidence statement is recorded in this case.

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 6 not met · 9 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PP4 PM5 PM2 PS1 PS2 PM1 PP5 PP1 PM6 PVS1 PS4 PM4 PS3 PP3 PM3 PP2

Benign

BP3 BP7 BS4 BS3 BP2 BP4 BP6 BS1 BP5 BA1 BS2 BP1

Met Not met Not assessed Not applicable

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.

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.

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.

Met · 2

PM2 SupportingThis 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). Details ▾Hide ▴

Rule

Absent/extremely rare allele frequency <0.00002 in gnomAD v4

Evidence considered

gnomAD v4.1: absent
gnomAD v2.1: absent
PM2_Supporting threshold: AF < 0.00002

Sources

evidence.json.results.gnomad.GNOMAD_V4_1evidence.json.results.gnomad.GNOMAD_V2_1MSH2/criteria.json

PP3 SupportingSpliceAI 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. Details ▾Hide ▴

Rule

Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >=0.2

Evidence considered

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

Sources

evidence.json.results.spliceaicase_summary.compact_evidence.spliceaiMSH2/criteria.json

Not met · 6 · evaluated, threshold not reached

BP7 This intronic duplication is located at c.793-11_794dup, which is 11 nucleotides upstream of the exon boundary. This does not meet the MSH2 BP7 positional requirement of at or beyond -21 in the intron. Details ▾Hide ▴

Rule

A synonymous or intronic variant at or beyond -21/+7

Evidence considered

Variant position: c.793-11_794dup
BP7 threshold for intronic variants: at or beyond -21

Sources

prefetch.normalize.variant_validatorMSH2/criteria.json

BP4 For intronic variants, BP4 requires SpliceAI to predict no splicing impact with a delta score of 0.1 or less. This variant has a maximum SpliceAI delta score of 0.71, which is above that threshold and does not support BP4. Details ▾Hide ▴

Rule

For intronic variants, SpliceAI predicts no splicing impact with delta score <=0.1

Evidence considered

SpliceAI max delta score: 0.71
BP4 threshold for intronic variants: <=0.1

Sources

evidence.json.results.spliceaicase_summary.compact_evidence.spliceaiMSH2/criteria.json

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. No such same-nucleotide precedent was identified for this variant. Details ▾Hide ▴

Rule

Same non-canonical splice nucleotide as a confirmed Pathogenic or Likely Pathogenic splice variant with similar or worse SpliceAI prediction

Evidence considered

No ClinVar record identified
No publications identified
No same-nucleotide VCEP precedent identified

Still missing

Established same-nucleotide pathogenic or likely pathogenic splice precedent

Sources

MSH2/criteria.jsonliterature_pass.jsonevidence.json.results.clinvar

BS1 BS1 requires a gnomAD v4 group maximum filtering allele frequency of at least 0.0001 and less than 0.001. This variant is absent from gnomAD v4.1, so its frequency is below the BS1 threshold. Details ▾Hide ▴

Rule

GnomAD v4 Grpmax filtering AF >=0.0001 and <0.001

Evidence considered

gnomAD v4.1: absent
BS1 threshold: >=0.0001 and <0.001

Sources

evidence.json.results.gnomad.GNOMAD_V4_1MSH2/criteria.json

BA1 BA1 requires a gnomAD v4 group maximum filtering allele frequency of at least 0.001. This variant is absent from gnomAD v4.1, so it is below the BA1 threshold. Details ▾Hide ▴

Rule

GnomAD v4 Grpmax filtering AF >=0.001

Evidence considered

gnomAD v4.1: absent
BA1 threshold: >=0.001

Sources

evidence.json.results.gnomad.GNOMAD_V4_1MSH2/criteria.json

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. SpliceAI predicts a possible splice effect with a maximum delta score of 0.71, but no constitutional RNA assay demonstrating a splice aberration with loss of the full-length transcript was identified, so current evidence does not meet the MSH2 VCEP PVS1 rule. Details ▾Hide ▴

Rule

For non-canonical splice variants, apply PVS1 only with qualifying constitutional RNA evidence demonstrating a pathogenic splice aberration

Evidence considered

MSH2 loss of function is an established disease mechanism
Generic PVS1 scaffold: not a default null-variant bucket
SpliceAI max delta score: 0.71
No RNA confirmation identified

Still missing

Constitutional RNA study showing variant-associated splice aberration and loss of full-length transcript
Independent confirmation if relying on a non-canonical splice defect

Sources

pvs1_gene_context.jsonpvs1_variant_assessment.jsonevidence.json.results.spliceaiMSH2/criteria.json

Not assessed · 9 · no assessment recorded

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. Details ▾Hide ▴

Rule

1 CRC/Endometrial MSI-H tumor or loss of MMR protein expression consistent with the variant location

Evidence considered

No tumor MSI/IHC evidence was provided
No relevant publications were identified

Still missing

Tumor MSI and/or IHC results consistent with MSH2 deficiency

Sources

case_summary.compact_evidenceliterature_pass.json

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

Rule

Lack of co-segregation with disease with combined Bayes Likelihood Ratio <=0.48

Evidence considered

No segregation data identified
No publications identified

Still missing

Pedigree-based segregation data with Bayes likelihood ratio

Sources

case_summary.jsonliterature_pass.json

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

Rule

No associated mRNA aberration for intronic variants or calibrated functional odds <=0.48

Evidence considered

No variant-specific functional or RNA publications identified

Still missing

Variant-specific constitutional RNA study with NMD inhibition
Variant-specific calibrated benign functional assay

Sources

vcep_materials.jsonliterature_pass.jsonMSH2/criteria.json

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

Rule

De novo points framework

Evidence considered

No de novo evidence identified
No tumor evidence identified

Still missing

Confirmed or assumed de novo data
Parental testing
Tumor MSI/IHC data

Sources

case_summary.jsonliterature_pass.jsonMSH2/criteria.json

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

Rule

Co-segregation with disease with combined Bayes Likelihood Ratio >2.08

Evidence considered

No segregation evidence identified

Still missing

Pedigree-based segregation data with Bayes likelihood ratio

Sources

case_summary.jsonliterature_pass.jsonMSH2/criteria.json

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

Rule

Tumor evidence inconsistent with the gene demonstrating genetic variation or MLH1 methylation/BRAF pattern

Evidence considered

No tumor phenotype data identified
No alternate molecular diagnosis identified

Still missing

Tumor MSS/IHC data inconsistent with MSH2 deficiency
Evidence for alternate molecular etiology

Sources

case_summary.jsonliterature_pass.jsonMSH2/criteria.json

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. Details ▾Hide ▴

Rule

Damaging functional evidence or qualifying RNA/monoallelic expression evidence

Evidence considered

No variant-specific functional or RNA publications identified

Still missing

Variant-specific calibrated damaging functional assay
Variant-specific constitutional RNA assay
Monoallelic expression data if available

Sources

vcep_materials.jsonliterature_pass.jsonMSH2/criteria.json

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. Details ▾Hide ▴

Rule

In-trans co-occurrence with a known pathogenic variant in a context arguing against CMMRD

Evidence considered

No qualifying in-trans co-occurrence data identified
No CMMRD clinical data identified

Still missing

Confirmed in-trans co-occurrence with a known pathogenic MSH2 variant
Clinical data excluding CMMRD

Sources

case_summary.jsonliterature_pass.jsonMSH2/criteria.jsonvcep_materials.json

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. Details ▾Hide ▴

Rule

Points-based in-trans evidence in a patient with clinical features consistent with CMMRD

Evidence considered

No qualifying in-trans CMMRD case data identified

Still missing

Confirmed in-trans co-occurrence with a pathogenic or likely pathogenic MSH2 variant
Clinical features consistent with CMMRD

Sources

case_summary.jsonliterature_pass.jsonMSH2/criteria.jsonvcep_materials.json

Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴

BP3 N/ABP3 is not used by the MSH2 VCEP for variant interpretation. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks BP3 as not applicable

Sources

MSH2/criteria.json

PM5 N/APM5 applies to missense substitutions at an amino acid residue with a different established pathogenic missense change. This variant is an intronic duplication and does not encode a missense substitution. Details ▾Hide ▴

Evidence considered

Protein consequence: p.?
Variant is intronic, not missense

Sources

case_summary.normalizationMSH2/criteria.json

BP2 N/ABP2 is not used by the MSH2 VCEP; BS2 is used instead for relevant co-occurrence evidence. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks BP2 as not applicable

Sources

MSH2/criteria.json

BP6 N/ABP6 is not used by this VCEP. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks BP6 as not applicable

Sources

MSH2/criteria.json

PM1 N/APM1 is not used for MSH2 because the VCEP does not recognize mutational hot spots suitable for classification purposes. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks PM1 as not applicable

Sources

MSH2/criteria.jsonvcep_materials.json

PP5 N/APP5 is not used by this VCEP. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks PP5 as not applicable

Sources

MSH2/criteria.json

PM6 N/APM6 is marked not applicable by the MSH2 VCEP. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks PM6 as not applicable

Sources

MSH2/criteria.json

PS4 N/APS4 is not used by the MSH2 VCEP because tumor evidence is incorporated through PP4 instead. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks PS4 as not applicable

Sources

MSH2/criteria.json

PM4 N/APM4 is not used by the MSH2 VCEP for protein length changes from in-frame variants. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks PM4 as not applicable

Sources

MSH2/criteria.json

BP1 N/ABP1 is not used by the MSH2 VCEP. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks BP1 as not applicable

Sources

MSH2/criteria.json

PP2 N/APP2 is not used by the MSH2 VCEP. Details ▾Hide ▴

Evidence considered

MSH2 VCEP marks PP2 as not applicable

Sources

MSH2/criteria.json

Identifiers

Gene: MSH2
Transcript: NM_000251.3
Coding (HGVS c.): NM_000251.3:c.793-11_794dup
Protein (HGVS p.): NP_000242.1:p.?
GRCh38: chr2:47414256 T>TTCTTAATTTTAGG
GRCh37: chr2:47641395 T>TTCTTAATTTTAGG

Gene diagram

Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.3. Select a row to find it on the plot.

MSH2NM_000251.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in MSH2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Rule

Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score >=0.2

Evidence considered

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

Sources

evidence.json.results.spliceaicase_summary.compact_evidence.spliceaiMSH2/criteria.json

Rule

A synonymous or intronic variant at or beyond -21/+7

Evidence considered

Variant position: c.793-11_794dup
BP7 threshold for intronic variants: at or beyond -21

Sources

prefetch.normalize.variant_validatorMSH2/criteria.json

Rule

For intronic variants, SpliceAI predicts no splicing impact with delta score <=0.1

Evidence considered

SpliceAI max delta score: 0.71
BP4 threshold for intronic variants: <=0.1

Sources

evidence.json.results.spliceaicase_summary.compact_evidence.spliceaiMSH2/criteria.json

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Captured SpliceAI source record Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

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

Somatic

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