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LYFE SCIENCES
Project: HERA
NM_000251.3:c.182A>C
p.Gln61Pro  ·  MSH2
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v4 ↗ cspec ↗
3

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.

PMID:17720936 ↗ PMID:20176959 ↗ PMID:33357406 ↗
4

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.

spliceai ↗ cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This 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).
gnomAD v4.1This 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 ↗ gnomAD v4 ↗
ClinVar evidence
02
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).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.72. BayesDel score = 0.0679979.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueQ61
Hotspots ↗