Back
LYFE SCIENCES
Project: HERA
NM_000179.3:c.3261del
p.Phe1088SerfsTer2  ·  MSH6
Starting
Initialising…
0%
Legacy Engine
Processing…
Classification rationale
1

The MSH6 NM_000179.3:c.3261del (NP_000170.1:p.(Phe1088SerfsTer2)) variant has been observed in somatic cancers in COSMIC (COSV52273658, n=132) and has been reported in ClinVar as Pathogenic, including an expert-panel assertion.

clinvar ↗
2

This variant is present at extremely low frequency in population databases, with gnomAD v4.1 allele frequency 1.42855e-05 (23/1610026 alleles; grpmax FAF 7.65e-06), which is below the MSH6 VCEP PM2 threshold of 0.00002, and it is absent from gnomAD-Canada v1.0.

cspec ↗ gnomad_v4 ↗ gnomad_canada ↗ gnomad_v2 ↗
3

This frameshift deletion is predicted to truncate MSH6 at codon 1088, and the active MSH6 VCEP specification applies PVS1 at Very Strong strength to nonsense or frameshift variants introducing a premature termination codon at or before codon 1341.

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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
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= 1.42412e-05; MAF= 0.00142%, 4/280876 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 9.68804e-05; MAF= 0.00969%, 1/10322 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.42855e-05; MAF= 0.00143%, 23/1610026 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 6.27825e-05; MAF= 0.00628%, 4/63712 alleles, homozygotes = 0); grpmax FAF= 7.65e-06.
gnomAD CanadaAbsent from gnomAD-Canada v1.0.
gnomAD v2 ↗ gnomAD v4 ↗ gnomAD 🇨🇦 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (31 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89363)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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; COSV52273658, n = 132 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueF1088
Hotspots ↗