About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.2034T>A, p.(Tyr678Ter)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
PVS1Very strong
PVS1 · very strong
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.
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched 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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions
2 Pathogenic.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
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 · 2 not met · 9 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MSH2 c.2034T>A (p.Tyr678Ter; p.Y678*) variant has been reported in ClinVar as pathogenic by 2 clinical laboratories.
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.
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.
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.
No criteria match.
Met · 2
PVS1 Very strongThis 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. Details ▾Hide ▴
Rule
Nonsense/frameshift variant introducing a premature termination codon at or before codon 891 in MSH2.
Evidence considered
- 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
Sources
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 in gnomAD v4 dataset.
Evidence considered
- Absent from gnomAD v4.1
- Absent from gnomAD v2.1
- MSH2 VCEP PM2 threshold: allele frequency <0.00002 in gnomAD v4
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v4.1 and therefore does not reach the BA1 threshold of at least 0.001. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.001.
Evidence considered
- Absent from gnomAD v4.1
- BA1 threshold >=0.001
Sources
BS1 This variant is absent from gnomAD v4.1 and therefore does not reach the BS1 threshold of at least 0.0001. Details ▾Hide ▴
Rule
GnomAD v4 grpmax filtering allele frequency >=0.0001 and <0.001.
Evidence considered
- Absent from gnomAD v4.1
- BS1 threshold >=0.0001
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo occurrence with confirmed parentage was identified for this variant. Details ▾Hide ▴
Rule
Requires qualifying de novo evidence scored under the VCEP point system.
Evidence considered
- MSH2 VCEP PS2 requires de novo points
Still missing
- Parental testing data
- De novo scoring information
Sources
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. Details ▾Hide ▴
Rule
Requires calibrated damaging functional evidence or other qualifying MMR functional assay evidence under the VCEP flowchart.
Evidence considered
- MMR VCEP functional assay framework reviewed
- No pathogenic functional assay result identified for this exact variant
Still missing
- Validated damaging functional assay result for this exact variant
- Constitutional RNA study showing a qualifying abnormal transcript if applicable
Sources
PM3 No confirmed biallelic or in trans observation relevant to the MSH2 VCEP PM3 scoring system was identified for this variant. Details ▾Hide ▴
Rule
Requires qualifying point-based in trans observations under the VCEP PM3 system.
Evidence considered
- MSH2 VCEP PM3 requires point-based in trans evidence
Still missing
- Phase-confirmed in trans observations
- CMMRD case details if present
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No pedigree data were identified showing co-segregation of this variant with Lynch syndrome-related disease. Details ▾Hide ▴
Rule
Co-segregation with disease in pedigree(s) with qualifying combined Bayes likelihood ratio.
Evidence considered
- MSH2 VCEP PP1 requires segregation evidence
Still missing
- Pedigree-level segregation data
- Calculated Bayes likelihood ratio
Sources
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. Details ▾Hide ▴
Rule
Requires MSI-H tumor and/or loss of MMR protein expression consistent with the variant location.
Evidence considered
- MSH2 VCEP PP4 requires Lynch syndrome-associated tumor evidence
Still missing
- Tumor MSI results
- MMR immunohistochemistry results
- Clinical phenotype details
Sources
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. Details ▾Hide ▴
Rule
Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a qualifying patient without evidence of CMMRD.
Evidence considered
- MSH2 VCEP BS2 requires in trans occurrence with a known pathogenic variant and no CMMRD features
Still missing
- Confirmed in trans observation
- Clinical data excluding CMMRD
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
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. Details ▾Hide ▴
Rule
Requires calibrated benign functional evidence or, for qualifying synonymous/intronic variants, RNA evidence showing no aberration.
Evidence considered
- MMR VCEP functional assay framework reviewed
- No benign functional result identified for this exact variant
Still missing
- Validated benign functional assay result for this exact variant
- Constitutional RNA study showing no relevant aberration if applicable
Sources
BS4 No segregation study or Bayes likelihood ratio was identified showing lack of co-segregation with disease. Details ▾Hide ▴
Rule
Lack of co-segregation with disease in pedigree(s) with qualifying combined Bayes likelihood ratio.
Evidence considered
- MSH2 VCEP BS4 requires non-segregation data
Still missing
- Pedigree-level segregation data
- Calculated Bayes likelihood ratio
Sources
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. Details ▾Hide ▴
Rule
Requires qualifying tumors with MSS/intact or inconsistent MMR findings, or MLH1-specific alternative explanations.
Evidence considered
- MSH2 VCEP BP5 requires contradictory tumor evidence
Still missing
- Tumor MSI results
- MMR immunohistochemistry results
- BRAF V600E or MLH1 methylation data if relevant
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AMSH2 VCEP PS1 applies to predicted missense substitutions encoding the same amino acid change, or to specific non-canonical splice nucleotide comparisons. This variant is a nonsense change, so PS1 does not apply. Details ▾Hide ▴
Rule
Same amino acid change by a different nucleotide change for missense variants, or same non-canonical splice nucleotide with similar or worse splice prediction.
Evidence considered
- Variant class is nonsense
- not missense or non-canonical splice
Sources
PS4 VCEPPS4 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
PM1 VCEPPM1 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
PM4 VCEPPM4 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
PM5 N/AThe MSH2 VCEP uses classic same-residue PM5 logic for missense variants. This variant is a nonsense change, so PM5 does not apply. Details ▾Hide ▴
Rule
Missense change at an amino acid residue where a different missense change has been classified as pathogenic or likely pathogenic on the protein level.
Evidence considered
- PM5 framework is classic same-residue missense
- pm5_candidates marked variant as not eligible for classic PM5 search
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
PP2 VCEPPP2 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
PP3 N/AMSH2 VCEP PP3 applies to missense variants with qualifying HCI prior values or to non-canonical splice variants with SpliceAI delta score at least 0.2. This variant is a nonsense change, and SpliceAI predicts no significant splice impact (max delta score 0.01), so PP3 does not apply. Details ▾Hide ▴
Rule
Missense variant with HCI prior >0.68 or non-canonical splice variant with SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta score 0.01
- No HCI prior entry was surfaced for this non-missense variant
Sources
PP5 VCEPPP5 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
BP1 VCEPBP1 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
BP2 VCEPBP2 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
BP4 N/AMSH2 VCEP BP4 applies to missense variants with an HCI prior below 0.11 or to qualifying intronic/synonymous variants with SpliceAI less than or equal to 0.1. This variant is a nonsense change, so BP4 does not apply. Details ▾Hide ▴
Rule
Missense variant with HCI prior <0.11, or qualifying intronic/synonymous variant with SpliceAI <=0.1.
Evidence considered
- SpliceAI max delta score 0.01
- No HCI prior entry was surfaced for this non-missense variant
- BayesDel score 0.66 is not the governing MSH2 VCEP rule for a nonsense variant
Sources
BP6 VCEPBP6 is not used in the MSH2 VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or qualifying intronic variants. This variant is a nonsense substitution, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond -21/+7 with no relevant splice concern.
Evidence considered
- Variant predicts p.(Tyr678Ter)
- SpliceAI max delta score 0.01
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.2034T>A
- Protein (HGVS p.)
- NP_000242.1:p.(Tyr678Ter)
- GRCh38
- chr2:47476395 T>A
- GRCh37
- chr2:47703534 T>A
- ClinVar
- 579638
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
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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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.660
How the predictions were used
PP3 N/AMSH2 VCEP PP3 applies to missense variants with qualifying HCI prior values or to non-canonical splice variants with SpliceAI delta score at least 0.2. This variant is a nonsense change, and SpliceAI predicts no significant splice impact (max delta score 0.01), so PP3 does not apply. Details ▾Hide ▴
Rule
Missense variant with HCI prior >0.68 or non-canonical splice variant with SpliceAI >=0.2.
Evidence considered
- SpliceAI max delta score 0.01
- No HCI prior entry was surfaced for this non-missense variant
Sources
BP4 N/AMSH2 VCEP BP4 applies to missense variants with an HCI prior below 0.11 or to qualifying intronic/synonymous variants with SpliceAI less than or equal to 0.1. This variant is a nonsense change, so BP4 does not apply. Details ▾Hide ▴
Rule
Missense variant with HCI prior <0.11, or qualifying intronic/synonymous variant with SpliceAI <=0.1.
Evidence considered
- SpliceAI max delta score 0.01
- No HCI prior entry was surfaced for this non-missense variant
- BayesDel score 0.66 is not the governing MSH2 VCEP rule for a nonsense variant
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants. This variant is a nonsense substitution, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond -21/+7 with no relevant splice concern.
Evidence considered
- Variant predicts p.(Tyr678Ter)
- SpliceAI max delta score 0.01
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 24362816 ↗Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.Thompson BA et al. · 2014No paper-specific finding is recorded.
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PMID 10946232 ↗Structure and function of mismatch repair proteins.No paper-specific finding is recorded.
-
PMID 11257106 ↗Deficient DNA mismatch repair: a common etiologic factor for colon cancer.No paper-specific finding is recorded.
-
PMID 15528792 ↗Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.No paper-specific finding is recorded.
-
PMID 23391514 ↗Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.No paper-specific finding is recorded.
-
PMID 7726159 ↗Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis.No paper-specific finding is recorded.
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PMID 8566964 ↗CpG dinucleotides in the hMSH2 and hMLH1 genes are hotspots for HNPCC mutations.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
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
Recorded maximum delta 0.010
Open source ↗
ClinVar
2 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1577628936
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/579638/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47703534-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47476395-T-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.2034…
- OncoKB ↗www.oncokb.org/gene/MSH2/Y678*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.2034T%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
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 has been reported in ClinVar as Pathogenic (2 clinical laboratories). (ClinVarID = 579638)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.