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LYFE SCIENCES
Project: HERA
NM_000179.3:c.4T>A
p.Ser2Thr  ·  MSH6
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Classification rationale
1

The MSH6 c.4T>A (p.Ser2Thr) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

clinvar ↗
2

This variant is absent from gnomAD v4.1 and gnomAD v2.1, which meets the MSH6 VCEP PM2 threshold for supporting evidence because the observed allele frequency is below 0.00002.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

For this MSH6 missense variant, the HCI prior probability is 0.0038, below the BP4 threshold of 0.11 and consistent with benign computational evidence; REVEL is 0.405 and BayesDel is -0.114406.

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
ClinVar evidence
02
ClinVar
This variant is absent from ClinVar.
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 possible splice impact for this variant (max delta score = 0.27). REVEL score = 0.405. BayesDel score = -0.114406. HCI prior probability for pathogenicity = 0.0038. MAPP score = 3.15. Custom PP2 score = 0.243.
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.
ResidueS2
Hotspots ↗