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.1 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 0.00002.2 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.3 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.4
Final classification
VUS
PM2
MSH2
c.182A>C
p.Gln61Pro
This variant
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.
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.
Classification rationale
PM2
VUS
MSH2 c.182A>C
PM2
→
VUS
3
PMID:17720936 ↗PMID:20176959 ↗PMID:33357406 ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchart
4
spliceai ↗revelbayesdelcspec ↗
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.
Gene diagram
· NM_000251.3 · variants mapped to exon structure
MSH2
NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
review
Pathogenic
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.
gnomAD v4.1 AF 3.11147e-06gnomAD v4.1 grpmax FAF 1.24e-06
Assessed · not applied
· 2 not met · 13 not assessed
Pathogenic
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.
PS2
No de novo observation with confirmed parentage was identified for this variant, so PS2 cannot be assessed.
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.
PM3
No biallelic case data or phase-confirmed observations were identified for this variant, so PM3 cannot be assessed.
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.
PP1
No co-segregation data or Bayes likelihood ratio were identified for this variant, so PP1 cannot be assessed.
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.
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.
Benign
BA1
The gnomAD v4.1 frequency is well below the BA1 threshold.
BS1
The gnomAD v4.1 frequency is far below the BS1 threshold.
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.
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.
BS4
No family-based non-segregation data or Bayes likelihood ratio were identified for this variant, so BS4 cannot be assessed.
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.
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.
N/A · 12
PVS1 · PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,606,956
0 hom · FAF 0.00012%
0 hom · FAF 0.00012%
European (non-Finnish) 5 / 1,177,842 |
0.00042% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00043%
· 1 / 232,376
0 hom
0 hom
European (non-Finnish) 1 / 103,276 |
0.00097% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links