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LYFE SCIENCES
Project: HERA
NM_000179.3:c.3483T>C
p.Pro1161=  ·  MSH6
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Classification rationale
1

The MSH6 NM_000179.3:c.3483T>C (NP_000170.1:p.(Pro1161=)) variant has been reported in ClinVar predominantly as likely benign or benign, with 4 likely benign and 1 benign clinical laboratory submissions.

clinvar ↗
2

This variant is rare in population databases, with gnomAD v4.1 overall AF 1.86e-06 (3/1,614,056 alleles) and highest observed subpopulation AF 3.20e-05 (2/62,482 alleles), which is below the MSH6 BS1 threshold of 0.00022 and BA1 threshold of 0.0022 but within the PM2_Supporting rarity threshold of <0.00002.

gnomad_v4 ↗ cspec ↗
3

This is a synonymous change, NP_000170.1:p.(Pro1161=), located 44 nucleotides from the exon 6 acceptor and 73 nucleotides from the donor, and SpliceAI predicts no splice effect (max delta score 0.00), supporting BP7 and BP4 rather than PP3.

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= 7.95551e-06; MAF= 0.00080%, 2/251398 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108743; MAF= 0.01087%, 2/18392 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.85867e-06; MAF= 0.00019%, 3/1614056 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20092e-05; MAF= 0.00320%, 2/62482 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 380626)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
ResidueP1161
Hotspots ↗