About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.1132del, p.(Glu378LysfsTer34)
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
NM_000251.3:c.1132del is a frameshift deletion in exon 7 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), well below the codon 891 threshold specified by the InSiGHT MMR VCEP for PVS1_VeryStrong in MSH2.
PM2Supporting
PM2 · supporting
NM_000251.3:c.1132del is absent from gnomAD v4.1, satisfying the InSiGHT VCEP PM2_Supporting criterion (allele frequency <0.00002, i.e., <1 in 50,000 alleles).
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.090 maximum delta
Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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.
29 criteria with recorded statuses: 2 met · 11 not met · 0 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000251.3:c.1132del is a frameshift deletion in exon 7 of MSH2 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), satisfying PVS1_VeryStrong per the InSiGHT MMR VCEP (PTC ≤ codon 891).
The variant is absent from gnomAD v4.1, satisfying PM2_Supporting per InSiGHT VCEP (allele frequency <0.00002).
No other pathogenic or benign criteria are met. The variant is absent from ClinVar; no tumor pathology, functional assay, segregation, or de novo data are available. The five publications reviewed are gene-level reviews that do not mention NM_000251.3:c.1132del.
Under the InSiGHT MMR VCEP combining rules, PVS1_VeryStrong requires at least 1 Strong, 2 Moderate, 1 Moderate + 1 Supporting, or 2 Supporting criteria in combination to reach Pathogenic; or 1 Moderate to reach Likely Pathogenic. With only PM2_Supporting in addition to PVS1_VeryStrong, none of these thresholds are met.
This variant is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MMR VCEP framework: 1 × PVS1_VeryStrong + 1 × PM2_Supporting does not satisfy any Pathogenic or Likely Pathogenic combining rule.
No criteria match.
Met · 2
PVS1 Very strongNM_000251.3:c.1132del is a frameshift deletion in exon 7 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), well below the codon 891 threshold specified by the InSiGHT MMR VCEP for PVS1_VeryStrong in MSH2. Details ▾Hide ▴
Evidence considered
- Frameshift deletion at c.1132 introduces PTC at codon 412
- which is ≤ codon 891 per InSiGHT VCEP PVS1 Appendix.
- MSH2 loss-of-function is an established disease mechanism for Lynch syndrome.
Sources
PM2 SupportingNM_000251.3:c.1132del is absent from gnomAD v4.1, satisfying the InSiGHT VCEP PM2_Supporting criterion (allele frequency <0.00002, i.e., <1 in 50,000 alleles). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (0 alleles).
- Also absent from gnomAD v2.1 and gnomAD-Canada v1.0.
Sources
Not met · 11 · evaluated, threshold not reached
PS2 No de novo observations for NM_000251.3:c.1132del were identified in ClinVar, the literature, or any reviewed source. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no de novo case reports identified in any of the five reviewed publications.
Still missing
- De novo status could not be assessed without parental genotype data.
PS3 The InSiGHT VCEP PS3 calibrated functional assay documentation is limited to missense, splice site, and synonymous variant types; no validated functional assay data exist for frameshift variants such as c.1132del. Details ▾Hide ▴
Evidence considered
- VCEP functional assay index restricts PS3/BS3 calibrated assays to missense
- splice site
- and synonymous variant types.
- No functional study testing c.1132del directly was found in any reviewed publication.
Still missing
- No calibrated functional assay applicable to frameshift deletions in MSH2.
Sources
vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchart
PP1 No co-segregation data are available for NM_000251.3:c.1132del in any reviewed source. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data were identified for this variant.
Still missing
- Co-segregation analysis requires pedigree data not present in the case materials.
PP3 No in silico evidence supports pathogenicity for this frameshift variant. SpliceAI max delta score is 0.09, which falls below the VCEP PP3 threshold of ≥0.2 for non-canonical splice predictions. HCI prior is not applicable to deletion variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.09
- below VCEP threshold of ≥0.2 for PP3_Supporting.
- HCI prior is not available for deletions (only missense substitutions).
- REVEL and BayesDel are not applicable to non-SNV variants.
Sources
PP4 No tumor MSI or IHC data are available for NM_000251.3:c.1132del to satisfy the InSiGHT VCEP PP4 criterion (≥1 CRC/endometrial MSI-H tumor with consistent MMR protein loss). Details ▾Hide ▴
Evidence considered
- No tumor pathology data provided for this variant in any reviewed source.
- Variant is absent from ClinVar with no associated phenotype submissions.
Still missing
- Tumor MSI/IHC data would be needed to evaluate PP4.
BA1 NM_000251.3:c.1132del is absent from gnomAD v4.1; allele frequency does not reach the BA1 threshold (≥0.1% Grpmax FAF). Details ▾Hide ▴
BS1 NM_000251.3:c.1132del is absent from gnomAD v4.1; allele frequency does not reach the InSiGHT VCEP BS1 threshold (≥0.01% and <0.1% Grpmax FAF, excluding founder variants). Details ▾Hide ▴
BS2 No evidence of co-occurrence in trans with a known pathogenic MSH2 variant was identified in any reviewed source. Details ▾Hide ▴
Evidence considered
- No case reports or family studies document this variant in trans with a pathogenic MSH2 variant.
Still missing
- Phase information and co-occurrence data would require parental testing or family studies.
BS3 The InSiGHT VCEP BS3 calibrated functional assay documentation is limited to missense, splice site, and synonymous variant types; no functional data demonstrating normal protein function exist for this frameshift variant. Details ▾Hide ▴
Evidence considered
- VCEP functional assay index restricts PS3/BS3 calibrated assays to missense
- splice site
- and synonymous variant types.
- No functional study assessing c.1132del was found in any reviewed publication.
Still missing
- No calibrated functional assay applicable to frameshift deletions in MSH2.
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No segregation data are available to demonstrate lack of co-segregation with disease for NM_000251.3:c.1132del. Details ▾Hide ▴
Evidence considered
- No pedigree or segregation data identified for this variant.
Still missing
- Segregation analysis requires pedigree data not present in the case materials.
BP5 No tumor data are available to demonstrate microsatellite stability, intact MMR protein expression, or an alternative molecular basis (e.g., BRAF V600E, MLH1 methylation) for tumors harboring NM_000251.3:c.1132del. Details ▾Hide ▴
Evidence considered
- No tumor pathology or molecular profiling data available for this variant.
Still missing
- Tumor MSS/IHC/methylation data would be needed to evaluate BP5.
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense variants encoding the same amino acid change as a known pathogenic variant, or to splice-site variants; NM_000251.3:c.1132del is a frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
PS4 VCEPThe InSiGHT MMR VCEP does not utilize PS4 for classification; tumor IHC data are captured under PP4 instead. Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPThe InSiGHT VCEP states there are no recognized mutational hotspots for classification purposes in MMR genes; PM1 is not applicable in this framework. Details ▾Hide ▴
Evidence considered
- InSiGHT VCEP: 'There are no recognized mutational hot spots that could be used for classification purposes.'
Sources
PM3 N/ASkipped by instruction; PM3 was flagged as trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 VCEPThe InSiGHT MMR VCEP does not utilize PM4. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies only to missense variants at an amino acid residue where a different missense change is classified as pathogenic; NM_000251.3:c.1132del is a frameshift deletion, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPThe InSiGHT MMR VCEP does not utilize PM6. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPThe InSiGHT MMR VCEP does not utilize PP2. Details ▾Hide ▴
No further detail was recorded.
PP5 VCEPThe InSiGHT MMR VCEP does not utilize PP5, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
No further detail was recorded.
BP1 VCEPThe InSiGHT MMR VCEP does not utilize BP1. Details ▾Hide ▴
No further detail was recorded.
BP2 VCEPThe InSiGHT MMR VCEP does not utilize BP2; BS2 is used instead. Details ▾Hide ▴
No further detail was recorded.
BP3 VCEPThe InSiGHT VCEP states BP3 is not applicable; it applies to in-frame deletions/insertions in repetitive regions without known function, which does not describe this frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
BP4 N/AThe InSiGHT VCEP BP4 rules apply only to missense variants (HCI prior <0.11) and intronic/synonymous variants (SpliceAI delta ≤0.1). NM_000251.3:c.1132del is a frameshift deletion; neither computational evidence pathway is applicable. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPThe InSiGHT MMR VCEP does not utilize BP6, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThe InSiGHT VCEP BP7 rule applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000251.3:c.1132del is a frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not part of the InSiGHT MMR VCEP framework (criteria set: PP4, BP3, BP7, BS4, BS3, PM5, BP2, PM2, BP4, BP6, PS1, PS2, BS1, PM1, PP5, PP1, BP5, PM6, BA1, PVS1, PS4, PM4, PS3, PP3, BS2, BP1, PP2). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.1132del
- Protein (HGVS p.)
- NP_000242.1:p.(Glu378LysfsTer34)
- GRCh38
- chr2:47429796 AG>A
- GRCh37
- chr2:47656935 AG>A
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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 No in silico evidence supports pathogenicity for this frameshift variant. SpliceAI max delta score is 0.09, which falls below the VCEP PP3 threshold of ≥0.2 for non-canonical splice predictions. HCI prior is not applicable to deletion variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.09
- below VCEP threshold of ≥0.2 for PP3_Supporting.
- HCI prior is not available for deletions (only missense substitutions).
- REVEL and BayesDel are not applicable to non-SNV variants.
Sources
BP4 N/AThe InSiGHT VCEP BP4 rules apply only to missense variants (HCI prior <0.11) and intronic/synonymous variants (SpliceAI delta ≤0.1). NM_000251.3:c.1132del is a frameshift deletion; neither computational evidence pathway is applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThe InSiGHT VCEP BP7 rule applies only to synonymous (silent) or intronic variants at or beyond -21/+7. NM_000251.3:c.1132del is a frameshift deletion. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
5 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
-
PMID 10946232 ↗Structure and function of mismatch repair proteins.Reviews the crystal structures of bacterial MutH, MutL, and MutS mismatch repair proteins. NM_000251.3:c.1132del was not identified in this paper.Does not name this variant
-
PMID 11257106 ↗Deficient DNA mismatch repair: a common etiologic factor for colon cancer.Reviews the genetics of HNPCC and deficient DNA mismatch repair, describing MLH1, MSH2, and MSH6 mutation spectra at the gene level. NM_000251.3:c.1132del was not identified in this paper.Does not name this variant
-
PMID 15528792 ↗Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.Updates the ICG-HNPCC/INSiGHT mutation database with 448 MMR gene mutations, reporting exonic distribution and mutation type frequencies for MSH2, MLH1, and MSH6. NM_000251.3:c.1132del was not identified in this paper.Does not name this variant
-
PMID 23391514 ↗Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.Reviews structural, molecular, and cellular functions of MSH2 and MSH6 in DNA mismatch repair, damage signaling, and noncanonical activities. NM_000251.3:c.1132del was not identified in this paper.Does not name this variant
-
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.Describes the InSiGHT 5-tiered classification scheme applied to 2,360 unique MMR gene variants in the locus-specific database. NM_000251.3:c.1132del was not identified in this paper.Does not name this variant
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 0.090
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_000251.3%3Ac.1132del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47656935-AG-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47429796-AG-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-47429796-AG-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.1132…
- OncoKB ↗www.oncokb.org/gene/MSH2/E378Kfs*34
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.1132del
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
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.