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LYFE SCIENCES
Project: HERA
NM_000179.3:c.3334G>A
p.Asp1112Asn  ·  MSH6
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Classification rationale
1

The MSH6 NM_000179.3:c.3334G>A (p.Asp1112Asn, p.D1112N) variant has been reported in ClinVar with predominantly uncertain significance submissions and a smaller number of likely benign submissions.

clinvar ↗
2

This variant is present in population databases, including gnomAD v4.1 at 76/1613996 alleles (AF 0.00004709; grpmax FAF 0.00004535) and gnomAD v2.1 at 8/282750 alleles (AF 0.00002829), and is absent from gnomAD-Canada; the gnomAD v4.1 frequency is above the MSH6 PM2 threshold of <0.00002 but below the BS1 threshold of 0.00022.

gnomad_v4 ↗ gnomad_v2 ↗ gnomad_canada ↗ cspec ↗
3

For MSH6 missense prediction, the HCI prior probability is 0.5901, which is below the PP3 thresholds of >0.68 and >0.81 and above the BP4 threshold of <0.11; REVEL is 0.71, BayesDel is -0.0786, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.04.

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
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Rule
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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= 2.82935e-05; MAF= 0.00283%, 8/282750 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.1978e-05; MAF= 0.00620%, 8/129078 alleles, homozygotes = 0); grpmax FAF= 2.855e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 4.70881e-05; MAF= 0.00471%, 76/1613996 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000128025; MAF= 0.01280%, 8/62488 alleles, homozygotes = 0); grpmax FAF= 4.535e-05.
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (14 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 220784)
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 = 0.04). REVEL score = 0.71. BayesDel score = -0.0786165. HCI prior probability for pathogenicity = 0.5901. MAPP score = 13.97. Custom PP2 score = 0.84.
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.
ResidueD1112
Hotspots ↗