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
MSH2
Final classification
VUS
MSH2 c.182A>C · p.Gln61Pro
MSH2
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 ↗
Gene diagram
· NM_000251.3 · variants mapped to exon structure
MSH2
NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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