About MSH2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MSH2 c.182A>C, p.(Gln61Pro)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in gnomAD v4.1 (5/1,606,956 alleles; AF 3.11e-06; highest population AF 4.25e-06 in European non-Finnish; grpmax FAF 1.24e-06), which is below the MSH2 PM2 threshold of 0.00002 (<1 in 50,000 alleles). This supports PM2_Supporting.
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: 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
5 / 1,606,956 alleles
gnomAD v4.1: 5 / 1,606,956 alleles. Recorded AF 3.11147e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.30337e-06; MAF= 0.00043%, 1/232376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.68279e-06; MAF= 0.00097%, 1/103276 alleles, homozygotes = 0).
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.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
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.
28 criteria with recorded statuses: 1 met · 2 not met · 13 not assessed · 12 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.182A>C (p.Gln61Pro) variant has not been observed in COSMIC and has been reported in ClinVar with conflicting interpretations, including uncertain significance and likely benign submissions.
This variant is present at extremely low frequency in gnomAD v4.1 (5/1,606,956 alleles; AF 3.11e-06; grpmax FAF 1.24e-06), which is below the InSiGHT MSH2 PM2_Supporting threshold of 0.00002.
Published MSH2 functional studies are cited for this variant class, but no verified variant-specific assay result or calibrated functional evidence was identified for p.(Gln61Pro), so PS3 and BS3 are not supported at this time.
In silico data show no meaningful predicted splice effect by SpliceAI (max delta 0.01), while missense predictors show a damage signal (REVEL 0.72; BayesDel 0.0679979); however, the MSH2 PP3/BP4 framework is based on HCI prior probabilities, which were not identified here.
No criteria match.
Met · 1
PM2 SupportingThis variant is present at extremely low frequency in gnomAD v4.1 (5/1,606,956 alleles; AF 3.11e-06; highest population AF 4.25e-06 in European non-Finnish; grpmax FAF 1.24e-06), which is below the MSH2 PM2 threshold of 0.00002 (<1 in 50,000 alleles). This supports PM2_Supporting. Details ▾Hide ▴
Rule
PM2_Supporting: absent or extremely rare in gnomAD v4 with AF <0.00002.
Evidence considered
- gnomAD v4.1 AF 3.11147e-06
- gnomAD v4.1 grpmax FAF 1.24e-06
Sources
Not met · 2 · evaluated, threshold not reached
BA1 The gnomAD v4.1 frequency is well below the BA1 threshold. The highest observed population frequency is 4.25e-06, which is below 0.001 and therefore does not support BA1. Details ▾Hide ▴
Rule
BA1 requires gnomAD v4 grpmax filtering allele frequency >=0.001.
Evidence considered
- Highest observed gnomAD v4.1 population AF 4.24505e-06
Sources
BS1 The gnomAD v4.1 frequency is far below the BS1 threshold. The highest observed population frequency is 4.25e-06, which is below the required threshold of at least 0.0001 and therefore does not support BS1. Details ▾Hide ▴
Rule
BS1 requires gnomAD v4 grpmax filtering allele frequency >=0.0001 and <0.001.
Evidence considered
- Highest observed gnomAD v4.1 population AF 4.24505e-06
Sources
Not assessed · 13 · no assessment recorded
PS1 No previously established Pathogenic or Likely Pathogenic variant encoding the same amino acid change was identified in the available materials, so PS1 cannot be assigned. Details ▾Hide ▴
Rule
PS1 requires the same amino acid substitution previously established by the VCEP as Pathogenic or Likely Pathogenic under the specified conditions.
Evidence considered
- PS1 requires same amino acid change previously established by the VCEP
Still missing
- Expert-panel classified same amino acid substitution from a different nucleotide change
- Evidence excluding a splice mechanism for any same-amino-acid comparator
Sources
PS2 No de novo observation with confirmed parentage was identified for this variant, so PS2 cannot be assessed. Details ▾Hide ▴
PS3 Published MSH2 functional studies are cited for this variant class, but no verified variant-specific calibrated assay result, OddsPath value, or flowchart-supported mismatch repair defect for p.(Gln61Pro) was identified to support PS3. Details ▾Hide ▴
Rule
PS3 requires calibrated functional evidence showing pathogenic odds above threshold or an MMR function defect under the accepted assay framework.
Evidence considered
- MMR functional assay documentation summary
- MMR functional assay flowchart
- Cited MSH2 functional literature without extractable variant-specific pathogenic result
Still missing
- Variant-specific functional assay result for p.Gln61Pro
- Calibration or flowchart-based evidence showing abnormal function
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchartPMID:17720936 ↗PMID:20176959 ↗PMID:33357406 ↗
PM3 No biallelic case data or phase-confirmed observations were identified for this variant, so PM3 cannot be assessed. Details ▾Hide ▴
Rule
PM3 requires sufficient point-based evidence from biallelic observations.
Evidence considered
- MSH2 PM3 is point-based for recessive/biallelic observations
Still missing
- Biallelic case observations
- Confirmed phase information
- PM3 point-based evidence
Sources
PM5 No MSH2 expert-panel Pathogenic or Likely Pathogenic missense variant at residue Gln61 was identified in the available materials, so PM5 cannot be assigned. Details ▾Hide ▴
Rule
PM5 requires a different missense change at the same residue previously classified by the VCEP as Pathogenic or Likely Pathogenic, with PP3 also met.
Evidence considered
- PM5 requires an alternate missense change at the same residue already classified by the VCEP
Still missing
- Expert-panel classified alternate missense change at residue Gln61
- Confirmation that any alternate missense effect is protein-based rather than splice-based
Sources
cspec ↗vcep_vcep_pilot_variants_mmr
PP1 No co-segregation data or Bayes likelihood ratio were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
Rule
PP1 requires co-segregation with disease meeting Bayes likelihood ratio thresholds.
Evidence considered
- MSH2 PP1 requires quantified co-segregation
Still missing
- Pedigree-based co-segregation data
- Combined Bayes likelihood ratio for segregation
Sources
PP3 For missense variants in this MSH2 framework, PP3 requires an HCI prior probability above 0.68 or 0.81 depending on strength, and that value was not identified. REVEL is 0.72 and BayesDel is 0.0679979, which are consistent with a missense-damage signal, but the official MSH2 PP3 rule is HCI-based. SpliceAI predicts no meaningful splice impact (max delta 0.01), so there is no computational support for a splice mechanism. Details ▾Hide ▴
Rule
For missense variants, PP3 requires HCI prior probability >0.68 or >0.81; for non-canonical splice variants, SpliceAI >=0.2 may apply.
Evidence considered
- REVEL 0.72
- BayesDel 0.0679979
- SpliceAI max delta 0.01
Still missing
- HCI prior probability result for p.Gln61Pro
Sources
PP4 No tumor MSI, immunohistochemistry, or phenotype data were identified to determine whether this variant is associated with Lynch syndrome features meeting the MSH2-specific PP4 thresholds. Details ▾Hide ▴
Rule
MSH2 PP4 requires 1 or more independent CRC/endometrial MSI-H tumors and/or loss of MMR protein expression consistent with the gene.
Evidence considered
- MSH2-specific PP4 rules require MSI-H tumor and/or MMR protein loss evidence
Still missing
- Tumor MSI results
- MMR immunohistochemistry results
- Clinical or family phenotype details relevant to Lynch syndrome
Sources
BS2 No confirmed in trans co-occurrence with a known pathogenic MSH2 variant and no accompanying age or CMMRD-exclusion data were identified, so BS2 cannot be assessed. Details ▾Hide ▴
Rule
BS2 requires confirmed in trans co-occurrence with a known pathogenic variant in an appropriate clinical context without evidence of CMMRD.
Evidence considered
- MSH2 BS2 requires in trans co-occurrence plus phenotype constraints
Still missing
- Confirmed in trans co-occurrence data
- Age at diagnosis
- Clinical evidence excluding CMMRD
Sources
cspec ↗vcep_table_for_cmmrd_diagnosis
BS3 Published MSH2 functional studies are cited for this variant class, but no verified variant-specific calibrated assay result or proficient function result for p.(Gln61Pro) was identified to support BS3. Details ▾Hide ▴
Rule
BS3 requires calibrated functional evidence showing low odds of pathogenicity or variant-specific proficient function under the MMR assay framework.
Evidence considered
- MMR functional assay documentation summary
- MMR functional assay flowchart
- Cited MSH2 functional literature without extractable variant-specific benign result
Still missing
- Variant-specific functional assay result for p.Gln61Pro
- Calibration or flowchart-based evidence showing normal function
Sources
cspec ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchartPMID:17720936 ↗PMID:20176959 ↗PMID:33357406 ↗
BS4 No family-based non-segregation data or Bayes likelihood ratio were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
Rule
BS4 requires lack of co-segregation with a combined Bayes likelihood ratio below the specified threshold.
Evidence considered
- MSH2 BS4 requires quantified lack of co-segregation
Still missing
- Pedigree-level segregation data
- Combined Bayes likelihood ratio for non-segregation
Sources
BP4 For missense variants in this MSH2 framework, BP4 requires an HCI prior probability of pathogenicity below 0.11, and that value was not identified. SpliceAI predicts no meaningful splice impact (max delta 0.01), but that intronic/synonymous splicing rule does not establish BP4 for this missense change. REVEL is 0.72 and BayesDel is 0.0679979, which do not support benign computational evidence. Details ▾Hide ▴
Rule
For missense variants, BP4 requires HCI prior probability <0.11; for intronic/synonymous variants, SpliceAI <=0.1 may apply.
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.72
- BayesDel 0.0679979
Still missing
- HCI prior probability result for p.Gln61Pro
Sources
BP5 No tumor evidence was identified showing microsatellite-stable disease, retained MMR protein expression, or MMR protein loss inconsistent with MSH2, so BP5 cannot be assessed. Details ▾Hide ▴
Rule
BP5 requires multiple tumors with MSS/retained expression or other tumor findings inconsistent with the gene under study.
Evidence considered
- MSH2 BP5 requires discordant tumor evidence
Still missing
- Tumor MSI status
- Tumor MMR immunohistochemistry results
- Tumor-specific findings inconsistent with MSH2 involvement
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, NM_000251.3:c.182A>C (p.Gln61Pro), and it does not fall into the MSH2 PVS1 null-variant categories of nonsense, frameshift, canonical +/-1 or 2 splice, or proven null splicing defect. SpliceAI predicts no significant splice impact (max delta score 0.01), so available evidence does not support a loss-of-function mechanism for PVS1. Details ▾Hide ▴
Rule
PVS1 in MSH2 applies to qualifying null variants or proven null splicing outcomes.
Evidence considered
- pvs1_gene_gate eligible at gene level
- variant bucket other
- SpliceAI max delta 0.01
Sources
PS4 N/APS4 is not applicable in this MSH2 framework. Details ▾Hide ▴
PM1 N/APM1 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks PM1 not applicable
Sources
cspec ↗vcep_mmr_functional_domains
PM4 N/APM4 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks PM4 not applicable
Sources
PM6 N/APM6 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks PM6 not applicable
Sources
PP2 N/APP2 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks PP2 not applicable
Sources
PP5 N/APP5 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks PP5 not applicable
Sources
BP1 N/ABP1 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks BP1 not applicable
Sources
BP2 N/ABP2 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks BP2 not applicable
Sources
BP3 N/ABP3 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks BP3 not applicable
Sources
BP6 N/ABP6 is not applicable in this MSH2 framework. Details ▾Hide ▴
Rule
Not applicable in the MSH2 InSiGHT specification.
Evidence considered
- InSiGHT MSH2 specification marks BP6 not applicable
Sources
BP7 N/AThis is a missense variant, not a synonymous or qualifying intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants at or beyond -21/+7.
Evidence considered
- c.182A>C predicts p.Gln61Pro
- SpliceAI max delta score 0.01
Sources
Identifiers
- Gene
- MSH2
- Transcript
- NM_000251.3
- Coding (HGVS c.)
- NM_000251.3:c.182A>C
- Protein (HGVS p.)
- NP_000242.1:p.(Gln61Pro)
- GRCh38
- chr2:47403373 A>C
- GRCh37
- chr2:47630512 A>C
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
5 / 1,606,956 alleles
AF 3.11e-06 · 0 homozygotes · FAF 1.24e-06
gnomAD v2.1
1 / 232,376 alleles
AF 4.3e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 3.1e-06 · 5 / 1,606,956 alleles · 0 hom · FAF 1.2e-06
| European (non-Finnish)5 / 1,177,842 | 4.2e-06 |
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.
gnomAD v2.1
AF 4.3e-06 · 1 / 232,376 alleles · 0 hom
| European (non-Finnish)1 / 103,276 | 9.7e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.11147e-06; MAF= 0.00031%, 5/1606956 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24505e-06; MAF= 0.00042%, 5/1177842 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.30337e-06; MAF= 0.00043%, 1/232376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.68279e-06; MAF= 0.00097%, 1/103276 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For missense variants in this MSH2 framework, PP3 requires an HCI prior probability above 0.68 or 0.81 depending on strength, and that value was not identified. REVEL is 0.72 and BayesDel is 0.0679979, which are consistent with a missense-damage signal, but the official MSH2 PP3 rule is HCI-based. SpliceAI predicts no meaningful splice impact (max delta 0.01), so there is no computational support for a splice mechanism. Details ▾Hide ▴
Rule
For missense variants, PP3 requires HCI prior probability >0.68 or >0.81; for non-canonical splice variants, SpliceAI >=0.2 may apply.
Evidence considered
- REVEL 0.72
- BayesDel 0.0679979
- SpliceAI max delta 0.01
Still missing
- HCI prior probability result for p.Gln61Pro
Sources
BP4 For missense variants in this MSH2 framework, BP4 requires an HCI prior probability of pathogenicity below 0.11, and that value was not identified. SpliceAI predicts no meaningful splice impact (max delta 0.01), but that intronic/synonymous splicing rule does not establish BP4 for this missense change. REVEL is 0.72 and BayesDel is 0.0679979, which do not support benign computational evidence. Details ▾Hide ▴
Rule
For missense variants, BP4 requires HCI prior probability <0.11; for intronic/synonymous variants, SpliceAI <=0.1 may apply.
Evidence considered
- SpliceAI max delta 0.01
- REVEL 0.72
- BayesDel 0.0679979
Still missing
- HCI prior probability result for p.Gln61Pro
Sources
BP7 N/AThis is a missense variant, not a synonymous or qualifying intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous or intronic variants at or beyond -21/+7.
Evidence considered
- c.182A>C predicts p.Gln61Pro
- SpliceAI max delta score 0.01
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.72. BayesDel score = 0.0679979.
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
5 / 1,606,956 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/90798/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-47630512-A-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-47403373-A-C?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000251.3%3Ac.182A…
- OncoKB ↗www.oncokb.org/gene/MSH2/Q61P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MSH2+c.182A%3EC
- 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= 3.11147e-06; MAF= 0.00031%, 5/1606956 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.24505e-06; MAF= 0.00042%, 5/1177842 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.30337e-06; MAF= 0.00043%, 1/232376 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.68279e-06; MAF= 0.00097%, 1/103276 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.72. BayesDel score = 0.0679979.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH2, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.
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.