About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.1147C>T, p.(Arg383Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
This variant is a nonsense change, NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*), in MSH2. Under the MSH2-specific ClinGen InSiGHT specification, nonsense variants introducing a premature termination codon at or before codon 891 meet PVS1 at very strong strength; this stop occurs at codon 383, well upstream of that threshold and is consistent with loss of function as an established disease mechanism.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%) with no homozygotes. This frequency is below the MSH2 PM2 threshold of 0.00002 (1 in 50,000 alleles), supporting PM2.
PP5Supporting
PP5 · supporting
Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
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.
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
2 / 1,614,058 alleles
gnomAD v4.1: 2 / 1,614,058 alleles. Recorded AF 1.23911e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from 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.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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: 3 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 NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*) variant has been reported in ClinVar and includes an expert panel Pathogenic classification.
This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%), which is below the MSH2 PM2 threshold of 0.00002.
This nonsense variant introduces a premature stop at codon 383, which is well upstream of the MSH2 codon 891 cutoff for very strong PVS1 evidence and is consistent with loss of function as an established disease mechanism for MSH2-related disease.
No criteria match.
Met · 3
PVS1 Very strongThis variant is a nonsense change, NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*), in MSH2. Under the MSH2-specific ClinGen InSiGHT specification, nonsense variants introducing a premature termination codon at or before codon 891 meet PVS1 at very strong strength; this stop occurs at codon 383, well upstream of that threshold and is consistent with loss of function as an established disease mechanism. Details ▾Hide ▴
Rule
MSH2 CSPEC PVS1 Very Strong for nonsense/frameshift variants introducing a premature termination codon at or before codon 891.
Evidence considered
- MSH2-specific PVS1 rule for nonsense variants at or before codon 891
- Variant consequence p.Arg383Ter / p.R383*
- MSH2 loss of function is an established disease mechanism in the active VCEP framework
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%) with no homozygotes. This frequency is below the MSH2 PM2 threshold of 0.00002 (1 in 50,000 alleles), supporting PM2. Details ▾Hide ▴
Rule
MSH2 CSPEC PM2 Supporting when allele frequency is <0.00002 in gnomAD v4.
Evidence considered
- Absent from gnomAD v2.1
- gnomAD v4.1 total AF 1.23911e-06
- MSH2 CSPEC PM2 threshold <0.00002
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant does not meet BA1 because the gnomAD v4.1 allele frequency is 1.23911e-06, which is far below the BA1 threshold of 0.001 (0.1%). Details ▾Hide ▴
Rule
MSH2 CSPEC BA1 stand-alone benign rule requires gnomAD v4 Grpmax filtering AF >=0.001.
Evidence considered
- gnomAD v4.1 total AF 1.23911e-06
- MSH2 CSPEC BA1 threshold >=0.001
Sources
BS1 This variant does not meet BS1 because the gnomAD v4.1 allele frequency is 1.23911e-06, which is well below the BS1 threshold of 0.0001 (0.01%). Details ▾Hide ▴
Rule
MSH2 CSPEC BS1 Strong requires gnomAD v4 Grpmax filtering AF >=0.0001 and <0.001.
Evidence considered
- gnomAD v4.1 total AF 1.23911e-06
- MSH2 CSPEC BS1 threshold >=0.0001 and <0.001
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo data were identified for this variant, so PS2 cannot be assessed. Details ▾Hide ▴
Rule
MSH2 CSPEC PS2 is points-based using confirmed or assumed de novo observations.
Evidence considered
- No de novo evidence was available
Still missing
- Confirmed maternity and paternity
- Parental testing
- Phenotype information needed for de novo points assignment
Sources
PS3 No variant-specific calibrated functional assay or RNA study demonstrating a damaging effect under the approved MMR assay framework was identified, so PS3 cannot be applied. Details ▾Hide ▴
Rule
MMR VCEP PS3 requires calibrated pathogenic functional evidence or qualifying RNA evidence under the approved assay framework.
Evidence considered
- MMR VCEP functional assay framework was reviewed
- No qualifying pathogenic functional data were available for this variant
Still missing
- Variant-specific calibrated protein assay data
- Variant-specific RNA assay data showing a qualifying abnormal effect
Sources
vcep_functional_assay_flowchartvcep_functional_assay_svi_documentation_mmr
PM3 No biallelic observation or points-based recessive evidence was identified for this variant, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
MSH2 CSPEC PM3 is points-based and requires observations consistent with a recessive disease context.
Evidence considered
- No qualifying PM3 evidence was available
Still missing
- Confirmed trans observations
- Case-level data needed for PM3 points assignment
Sources
PP1 No co-segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
MSH2 CSPEC PP1 requires co-segregation with disease with strength determined by Bayes likelihood ratio.
Evidence considered
- No segregation evidence was available
Still missing
- Pedigree-level segregation data
- Bayes likelihood ratio for co-segregation
Sources
PP4 No tumor microsatellite instability result, mismatch repair immunohistochemistry result, or other phenotype data were identified to determine whether the clinical findings meet the MSH2-specific PP4 criteria. Details ▾Hide ▴
Rule
MSH2 CSPEC PP4 is based on MSI-H tumors and/or loss of MMR protein expression consistent with the variant gene, with graded strength by number of independent tumors.
Evidence considered
- MSH2 PP4 requires tumor or phenotype-specific evidence under CSPEC
- No qualifying phenotype details were available
Still missing
- Tumor MSI status
- MMR IHC pattern
- Clinical phenotype details relevant to Lynch syndrome or CMMRD
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS2 No confirmed in trans co-occurrence data with a pathogenic MSH2 variant in an individual without features of constitutional mismatch repair deficiency were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
MSH2 CSPEC BS2 requires confirmed in trans co-occurrence with a pathogenic variant in an appropriate clinical context.
Evidence considered
- No qualifying in trans co-occurrence data were available
Still missing
- Confirmed phase with a pathogenic variant
- Clinical assessment for absence of CMMRD features
- Relevant age and tumor phenotype information
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No variant-specific calibrated functional assay or RNA study demonstrating retained function or no mRNA abnormality was identified, so BS3 cannot be applied. Details ▾Hide ▴
Rule
MMR VCEP BS3 requires calibrated benign functional evidence or normal RNA findings under the approved assay framework.
Evidence considered
- MMR VCEP functional assay framework was reviewed
- No qualifying benign functional data were available for this variant
Still missing
- Variant-specific calibrated protein assay data
- Variant-specific RNA assay data showing no abnormal transcript effect
Sources
vcep_functional_assay_flowchartvcep_functional_assay_svi_documentation_mmr
BS4 No segregation data were identified showing lack of co-segregation with disease, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
MSH2 CSPEC BS4 requires lack of co-segregation with disease with a defined Bayes likelihood ratio threshold.
Evidence considered
- No family non-segregation data were available
Still missing
- Pedigree-level segregation data
- Bayes likelihood ratio for non-segregation
Sources
BP5 No tumor data were identified showing mismatch repair findings inconsistent with MSH2 involvement, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
MSH2 CSPEC BP5 is based on multiple tumors showing molecular findings inconsistent with the gene harboring the variant.
Evidence considered
- No qualifying contradictory tumor evidence was available
Still missing
- Tumor MSS/MSI data
- MMR IHC data
- BRAF V600E or MLH1 methylation data where relevant
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this criterion is defined here for predicted missense substitutions encoding the same amino acid change, or for non-canonical splice variants affecting the same nucleotide as an established splice variant. This variant is a nonsense substitution. Details ▾Hide ▴
Rule
MSH2 CSPEC PS1 applies to missense same-amino-acid substitutions or qualifying non-canonical splice variants.
Evidence considered
- Variant consequence is nonsense
Sources
PS4 N/APS4 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
PM1 N/APM1 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
cspec ↗vcep_mmr_functional_domains
PM4 N/APM4 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
PM5 N/APM5 is not applicable because this is a nonsense variant, not a missense substitution at a residue with another established pathogenic or likely pathogenic missense change. Details ▾Hide ▴
Rule
MSH2 CSPEC PM5 applies to missense variants only.
Evidence considered
- Variant consequence is nonsense rather than missense
Sources
PM6 N/APM6 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
PP2 N/APP2 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
PP3 N/APP3 is not applicable because the MSH2 specification uses this criterion for missense variants with elevated HCI prior probability or for non-canonical splice variants with SpliceAI >=0.2. This variant is a nonsense substitution. No HCI prior or REVEL score was available, and the available BayesDel score does not establish PP3 for this variant type under the active MSH2 rules. Details ▾Hide ▴
Rule
MSH2 CSPEC PP3 applies to missense variants with HCI prior >0.68 or non-canonical splice variants with SpliceAI >=0.2.
Evidence considered
- Variant consequence is nonsense
- HCI prior not found for this substitution
- REVEL not found
- BayesDel score 0.66
Sources
BP1 N/ABP1 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
BP2 N/ABP2 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
BP3 N/ABP3 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
BP4 N/ABP4 is not applicable because the MSH2 specification uses this criterion for missense variants with low HCI prior probability or for synonymous/intronic variants with SpliceAI <=0.1. This variant is a nonsense substitution. A BayesDel score of 0.66 was available, but this does not establish BP4 for this variant type under the active MSH2 rules. Details ▾Hide ▴
Rule
MSH2 CSPEC BP4 applies to missense variants with HCI prior <0.11 or synonymous/intronic variants with SpliceAI <=0.1.
Evidence considered
- Variant consequence is nonsense
- BayesDel score 0.66
- MSH2 CSPEC BP4 rule is limited to missense or synonymous/intronic contexts
Sources
cspec ↗bayesdel
BP6 N/ABP6 is not applicable under the MSH2 specification. Details ▾Hide ▴
Rule
Not applicable in MSH2 CSPEC.
Evidence considered
- Criterion marked not applicable by MSH2 CSPEC
Sources
BP7 N/ABP7 is not applicable because this variant is not synonymous or intronic. Details ▾Hide ▴
Rule
MSH2 CSPEC BP7 applies to synonymous or qualifying intronic variants.
Evidence considered
- Variant is exonic nonsense
Sources
PVS1_generic_framework N/AA gene-specific MSH2 PVS1 rule is available and was used, so the generic PVS1 framework is not the primary adjudication rule for this case. Details ▾Hide ▴
Rule
Gene-specific PVS1 guidance takes precedence over generic fallback guidance.
Evidence considered
- Gene-specific PVS1 rule available in MSH2 CSPEC
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.1147C>T
- Protein (HGVS p.)
- NP_000242.1:p.(Arg383Ter)
- GRCh38
- chr2:47429812 C>T
- GRCh37
- chr2:47656951 C>T
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
—
Transcript span
—
Strand
—
Variants mapped
—
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
2 / 1,614,058 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,614,058 alleles · 0 hom
| South Asian1 / 91,056 | 1.1e-05 |
| European (non-Finnish)1 / 1,180,020 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.23911e-06; MAF= 0.00012%, 2/1614058 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09823e-05; MAF= 0.00110%, 1/91056 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APP3 is not applicable because the MSH2 specification uses this criterion for missense variants with elevated HCI prior probability or for non-canonical splice variants with SpliceAI >=0.2. This variant is a nonsense substitution. No HCI prior or REVEL score was available, and the available BayesDel score does not establish PP3 for this variant type under the active MSH2 rules. Details ▾Hide ▴
Rule
MSH2 CSPEC PP3 applies to missense variants with HCI prior >0.68 or non-canonical splice variants with SpliceAI >=0.2.
Evidence considered
- Variant consequence is nonsense
- HCI prior not found for this substitution
- REVEL not found
- BayesDel score 0.66
Sources
BP4 N/ABP4 is not applicable because the MSH2 specification uses this criterion for missense variants with low HCI prior probability or for synonymous/intronic variants with SpliceAI <=0.1. This variant is a nonsense substitution. A BayesDel score of 0.66 was available, but this does not establish BP4 for this variant type under the active MSH2 rules. Details ▾Hide ▴
Rule
MSH2 CSPEC BP4 applies to missense variants with HCI prior <0.11 or synonymous/intronic variants with SpliceAI <=0.1.
Evidence considered
- Variant consequence is nonsense
- BayesDel score 0.66
- MSH2 CSPEC BP4 rule is limited to missense or synonymous/intronic contexts
Sources
cspec ↗bayesdel
BP7 N/ABP7 is not applicable because this variant is not synonymous or intronic. Details ▾Hide ▴
Rule
MSH2 CSPEC BP7 applies to synonymous or qualifying intronic variants.
Evidence considered
- Variant is exonic nonsense
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). BayesDel score = 0.66.
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
2 / 1,614,058 recorded alleles
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 ↗
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/90554/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47656951-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47429812-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.1147…
- OncoKB ↗www.oncokb.org/gene/MSH2/R383*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=104732118
- 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
This variant is present in gnomAD v4.1 (AF= 1.23911e-06; MAF= 0.00012%, 2/1614058 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09823e-05; MAF= 0.00110%, 1/91056 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). 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 previously been reported in somatic cancers (COSMIC; COSV51878760, n = 9 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.