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LYFE SCIENCES
Project: HERA
NM_000179.3:c.-2G>T
p.?  ·  MSH6
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Classification rationale
1

The MSH6 NM_000179.3:c.-2G>T (NP_000170.1:p.?) variant has not been observed in COSMIC and has been reported in ClinVar with mixed single-submitter interpretations, including uncertain significance and likely benign.

clinvar ↗
2

This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 1.24133e-05 (20/1611176 alleles) and gnomAD v2.1 total allele frequency 1.45244e-05 (4/275398 alleles), which supports PM2_Supporting under the MSH6 VCEP threshold of less than 0.00002.

gnomad_v4 ↗ gnomad_v2 ↗ cspec ↗
3

Available evidence does not show a qualifying constitutional RNA or other calibrated functional study for this variant, so PS3 and BS3 are not currently supported.

cspec ↗ PMID:26888055 ↗
4

SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.00, but this 5′ UTR substitution does not fit the MSH6 VCEP PP3 or BP4 rule types for missense or qualifying intronic/non-canonical splice variants.

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= 1.45244e-05; MAF= 0.00145%, 4/275398 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141084; MAF= 0.01411%, 1/7088 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.24133e-05; MAF= 0.00124%, 20/1611176 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.0002404; MAF= 0.02404%, 15/62396 alleles, homozygotes = 0); grpmax FAF= 2.987e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 142219)
ClinVar ↗
03
Functional
No functional summary recorded.
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 has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
06
Cancer hotspots
No cancer hotspot summary recorded.