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LYFE SCIENCES
Project: HERA
NM_000179.3:c.199C>A
p.Pro67Thr  ·  MSH6
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Classification rationale
1

The MSH6 c.199C>A (p.Pro67Thr) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with mostly uncertain significance submissions and one benign submission.

clinvar ↗
2

This variant is extremely rare in gnomAD v4.1, where it is present in 1 of 1,501,316 alleles (AF 6.66082e-07) with a highest observed population frequency of 8.86721e-07 in non-Finnish Europeans, which is below the MSH6 PM2_Supporting threshold of 0.00002.

gnomad_v4 ↗ cspec ↗
3

SpliceAI predicts no significant splice impact for this variant (max delta score 0.00), and additional computational scores are low or benign-leaning (REVEL 0.161; BayesDel -0.32103), although the MSH6 VCEP missense PP3/BP4 rule requires an HCI prior probability that was not available 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= 9.50408e-06; MAF= 0.00095%, 1/105218 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.31267e-05; MAF= 0.00231%, 1/43240 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.66082e-07; MAF= 0.00007%, 1/1501316 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.86721e-07; MAF= 0.00009%, 1/1127750 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Benign (1 clinical laboratory) 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. MSH6, 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 = 0.00). REVEL score = 0.161. BayesDel score = -0.32103.
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.
ResidueP67
Hotspots ↗