About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.1661+1G>A, p.?
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 affects the canonical +1 donor splice nucleotide in MSH2. Under the MSH2 InSiGHT specification, canonical ±1,2 splice variants can meet PVS1 at very strong strength when loss of function is an established disease mechanism and the predicted splice consequence is expected to create a null transcript; the available MSH2 PVS1 assessments support full-strength application for this variant. PP3 was not added because the same predicted splice effect should not be double-counted.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,612,780 alleles; AF 6.20e-07, 0 homozygotes), which is below the MSH2 VCEP PM2 threshold of 0.00002 (1 in 50,000 alleles). This supports PM2 at supporting strength.
PP5Supporting
PP5 · supporting
Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Likely 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
1 / 1,612,780 alleles
gnomAD v4.1: 1 / 1,612,780 alleles. Recorded AF 6.20047e-07. 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.
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: 3 met · 3 not met · 9 not assessed · 13 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.1661+1G>A (NP_000242.1:p.?) variant has been reported in ClinVar, including an InSiGHT expert panel classification of likely pathogenic and additional pathogenic/likely pathogenic clinical laboratory submissions.
This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 (1/1,612,780 alleles; AF 6.20e-07), which is below the MSH2 VCEP PM2 threshold of 0.00002.
SpliceAI predicts a strong splice effect for this canonical donor variant (max delta score 0.97), supporting predicted disruption of normal splicing; however, this computational evidence was not counted separately because the same splice effect is captured under PVS1 for a canonical +1 splice-site variant.
No criteria match.
Met · 3
PVS1 Very strongThis variant affects the canonical +1 donor splice nucleotide in MSH2. Under the MSH2 InSiGHT specification, canonical ±1,2 splice variants can meet PVS1 at very strong strength when loss of function is an established disease mechanism and the predicted splice consequence is expected to create a null transcript; the available MSH2 PVS1 assessments support full-strength application for this variant. PP3 was not added because the same predicted splice effect should not be double-counted. Details ▾Hide ▴
Rule
MSH2 VCEP PVS1 very strong rule for IVS±1/2 splice variants expected to disrupt the reading frame and undergo NMD.
Evidence considered
- Canonical +1 splice donor variant
- MSH2 loss of function is an established disease mechanism in the applied VCEP framework
- Variant-level PVS1 scaffold suggests full-strength PVS1
Still missing
- Direct RNA evidence for the exact variant was not confirmed from the available sources.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and present only once in gnomAD v4.1 (1/1,612,780 alleles; AF 6.20e-07, 0 homozygotes), which is below the MSH2 VCEP PM2 threshold of 0.00002 (1 in 50,000 alleles). This supports PM2 at supporting strength. Details ▾Hide ▴
Rule
Absent/extremely rare allele frequency <0.00002 in gnomAD v4 dataset.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 total AF 6.20e-07
Sources
Not met · 3 · evaluated, threshold not reached
BA1 The population frequency does not reach the benign stand-alone threshold. In gnomAD v4.1 this variant is present at 1/1,612,780 alleles (AF 6.20e-07), which is below the BA1 threshold of 0.001. Details ▾Hide ▴
Rule
BA1 requires gnomAD v4 grpmax filtering allele frequency >=0.001.
Evidence considered
- gnomAD v4.1 total AF 6.20e-07
Sources
BS1 The population frequency does not reach the benign strong threshold. In gnomAD v4.1 this variant is present at 1/1,612,780 alleles (AF 6.20e-07), which is below the BS1 threshold of 0.0001. Details ▾Hide ▴
Rule
BS1 requires gnomAD v4 grpmax filtering allele frequency >=0.0001 and <0.001.
Evidence considered
- gnomAD v4.1 total AF 6.20e-07
Sources
BP4 Available computational evidence does not support no splice impact. SpliceAI predicts a strong splice effect for this intronic variant (max delta score 0.97), which is well above the MSH2 VCEP BP4 threshold of 0.1 for intronic variants predicted to have no splicing impact. A BayesDel score of 0.66 is available, but the VCEP intronic computational rule is based on SpliceAI. Details ▾Hide ▴
Rule
For intronic variants, BP4 requires SpliceAI delta <=0.1.
Evidence considered
- SpliceAI max delta score 0.97
- BayesDel score 0.66
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence was identified for this variant. The available evidence does not support PS2. Details ▾Hide ▴
Rule
PS2 requires de novo points under the MSH2 VCEP scoring system.
Evidence considered
- VCEP de novo scoring framework reviewed
Still missing
- No maternity/paternity-confirmed de novo report identified
Sources
PS3 No validated variant-specific functional or RNA assay result was confirmed for this exact variant from the available evidence. Although splice studies are relevant for MMR splice-site variants, no direct assay result was verified here to support PS3. Details ▾Hide ▴
Rule
PS3 requires calibrated pathogenic functional evidence or qualifying MMR functional assay flowchart evidence.
Evidence considered
- MMR VCEP functional assay guidance reviewed
- No exact confirmed assay result identified
Still missing
- Direct patient RNA study
- minigene assay
- or other validated functional assay for this exact variant was not confirmed.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchartPMID:16142001 ↗PMID:18561205 ↗PMID:25741868 ↗
PM3 No evidence was identified that this variant occurred in trans with a pathogenic MSH2 variant in a case informative for CMMRD scoring. The available evidence does not support PM3. Details ▾Hide ▴
Rule
PM3 requires points from informative trans observations.
Evidence considered
- VCEP PM3 points framework reviewed
Still missing
- No confirmed in trans observations identified
- No CMMRD-relevant case details identified
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
PP1 No segregation data were identified to calculate a Bayes likelihood ratio for co-segregation with disease. The available evidence does not support PP1 at this time. Details ▾Hide ▴
Rule
PP1 requires a combined Bayes likelihood ratio >2.08, with strength based on the total score.
Evidence considered
- VCEP segregation thresholds reviewed
Still missing
- No pedigree-level segregation data identified
Sources
PP4 No tumor microsatellite instability result, mismatch repair immunohistochemistry result, or other phenotype data were identified to determine whether the MSH2 VCEP PP4 phenotype thresholds are met. Details ▾Hide ▴
Rule
PP4 in this VCEP depends on qualifying MSI-H and/or MMR protein loss findings, with separate strengths by number of independent tumors.
Evidence considered
- VCEP PP4 criteria reviewed
Still missing
- No MSI data identified
- No IHC data identified
- No phenotype or family-based CMMRD scoring information identified
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS2 No confirmed observation in trans with a known pathogenic MSH2 variant in a person whose clinical features argue against CMMRD was identified. The available evidence does not support BS2. Details ▾Hide ▴
Rule
BS2 requires a qualifying in trans observation with clinical features arguing against CMMRD.
Evidence considered
- VCEP BS2 rule reviewed
Still missing
- No phase-confirmed trans observation identified
- No age/phenotype data sufficient for the BS2 rule identified
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 No well-established study showing normal splicing or preserved MSH2 function for this exact variant was confirmed. The available evidence does not support BS3. Details ▾Hide ▴
Rule
BS3 requires calibrated benign functional evidence or qualifying normal RNA/protein assay evidence.
Evidence considered
- MMR VCEP functional assay guidance reviewed
- No exact benign functional assay result identified
Still missing
- Direct evidence of normal transcript processing or preserved function for this exact variant was not confirmed.
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchartPMID:16142001 ↗PMID:18561205 ↗PMID:25741868 ↗
BS4 No non-segregation data were identified to calculate a Bayes likelihood ratio arguing against pathogenicity. The available evidence does not support BS4 at this time. Details ▾Hide ▴
Rule
BS4 requires a combined Bayes likelihood ratio <=0.48, with strength based on the total score.
Evidence considered
- VCEP segregation thresholds reviewed
Still missing
- No informative non-segregation data identified
Sources
BP5 No tumor findings were identified that are inconsistent with MSH2-related mismatch repair deficiency. The available evidence is insufficient to assess BP5. Details ▾Hide ▴
Rule
BP5 requires specified numbers of tumors with MSS and/or inconsistent MMR protein loss patterns.
Evidence considered
- VCEP BP5 rule reviewed
Still missing
- No MSS or inconsistent IHC tumor data identified
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AThis criterion is designed for predicted missense substitutions or non-canonical splice nucleotides matched to previously established splice variants. This variant is a canonical +1 splice donor change, so PS1 is not applicable. Details ▾Hide ▴
Rule
PS1 in this VCEP applies to same amino acid missense changes or same non-canonical splice nucleotides.
Evidence considered
- Variant type is canonical splice donor
Sources
PS4 N/APS4 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
PM1 N/APM1 is not applicable in this VCEP framework for this variant. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
PM4 N/APM4 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
PM5 N/APM5 applies to missense variants at amino acid residues with established pathogenic or likely pathogenic missense substitutions. This is not a missense variant. Details ▾Hide ▴
Rule
PM5 is restricted to missense variants.
Evidence considered
- Variant type is splice-site
- not missense
Sources
PM6 N/APM6 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
PP2 N/APP2 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
PP3 N/ASpliceAI predicts a strong splice effect for this variant (max delta score 0.97), but the MSH2 VCEP PP3 splice rule applies to non-canonical splicing nucleotides. This is a canonical +1 splice-site variant, and the same splice prediction evidence should not be stacked with PVS1. Details ▾Hide ▴
Rule
PP3 splice rule is limited to non-canonical splicing nucleotides with SpliceAI delta >=0.2.
Evidence considered
- SpliceAI max delta score 0.97
- BayesDel score 0.66 available but not used for the VCEP splice rule
Sources
BP1 N/ABP1 is not applicable in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
BP2 N/ABP2 is not used in this VCEP framework; BS2 is used instead when relevant. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
BP3 N/ABP3 is not used in this VCEP framework and is not applicable to this variant. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
BP6 N/ABP6 is not for use in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP.
Evidence considered
- Criterion marked not applicable by VCEP
Sources
BP7 N/ABP7 applies to synonymous or deep intronic variants at or beyond -21/+7. This variant is at the canonical +1 splice donor nucleotide, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants at or beyond -21/+7.
Evidence considered
- Variant position is +1 splice donor
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.1661+1G>A
- Protein (HGVS p.)
- NP_000242.1:p.?
- GRCh38
- chr2:47466809 G>A
- GRCh37
- chr2:47693948 G>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
1 / 1,612,780 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,612,780 alleles · 0 hom
| European (non-Finnish)1 / 1,179,122 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20047e-07; MAF= 0.00006%, 1/1612780 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.48089e-07; MAF= 0.00008%, 1/1179122 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 Available computational evidence does not support no splice impact. SpliceAI predicts a strong splice effect for this intronic variant (max delta score 0.97), which is well above the MSH2 VCEP BP4 threshold of 0.1 for intronic variants predicted to have no splicing impact. A BayesDel score of 0.66 is available, but the VCEP intronic computational rule is based on SpliceAI. Details ▾Hide ▴
Rule
For intronic variants, BP4 requires SpliceAI delta <=0.1.
Evidence considered
- SpliceAI max delta score 0.97
- BayesDel score 0.66
Sources
PP3 N/ASpliceAI predicts a strong splice effect for this variant (max delta score 0.97), but the MSH2 VCEP PP3 splice rule applies to non-canonical splicing nucleotides. This is a canonical +1 splice-site variant, and the same splice prediction evidence should not be stacked with PVS1. Details ▾Hide ▴
Rule
PP3 splice rule is limited to non-canonical splicing nucleotides with SpliceAI delta >=0.2.
Evidence considered
- SpliceAI max delta score 0.97
- BayesDel score 0.66 available but not used for the VCEP splice rule
Sources
BP7 N/ABP7 applies to synonymous or deep intronic variants at or beyond -21/+7. This variant is at the canonical +1 splice donor nucleotide, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants at or beyond -21/+7.
Evidence considered
- Variant position is +1 splice donor
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.97). 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
1 / 1,612,780 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 ↗
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/90719/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47693948-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47466809-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.1661…
- OncoKB ↗www.oncokb.org/gene/MSH2/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.1661+1G%3EA
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= 6.20047e-07; MAF= 0.00006%, 1/1612780 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.48089e-07; MAF= 0.00008%, 1/1179122 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Likely pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.97). BayesDel score = 0.66.
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).