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LYFE SCIENCES
Project: HERA
NM_000179.3:c.942C>G
p.Ser314Arg  ·  MSH6
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Classification rationale
1

The MSH6 c.942C>G (p.Ser314Arg) variant has been reported in ClinVar, where most submissions are classified as likely benign or benign, with additional submissions classified as uncertain significance.

clinvar ↗
2

In gnomAD v4.1, this variant is present at an overall allele frequency of 0.0000223049 (36/1613998 alleles), and the grpmax filtering allele frequency is 0.00027673, which is above the MSH6 BS1 threshold of 0.00022 and below the BA1 threshold of 0.0022.

gnomad_v4 ↗ cspec ↗
3

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00; however, no HCI prior probability result was identified to support missense PP3 or BP4 assessment under the MSH6 specification.

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
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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= 5.30632e-05; MAF= 0.00531%, 15/282682 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000561167; MAF= 0.05612%, 14/24948 alleles, homozygotes = 0); grpmax FAF= 0.00037952.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 2.23049e-05; MAF= 0.00223%, 36/1613998 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000387121; MAF= 0.03871%, 29/74912 alleles, homozygotes = 0); grpmax FAF= 0.00027673.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Uncertain significance (4 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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 = 0.188. BayesDel score = -0.304016.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99316054, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueS314
Hotspots ↗