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LYFE SCIENCES
Project: HERA
NM_000251.3:c.1147C>T
p.Arg383Ter  ·  MSH2
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Classification rationale
1

The MSH2 NM_000251.3:c.1147C>T (p.Arg383Ter; p.R383*) variant has been reported in ClinVar and includes an expert panel Pathogenic classification.

clinvar ↗
2

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 2/1614058 alleles (AF 1.23911e-06; 0.00012%), which is below the MSH2 PM2 threshold of 0.00002.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

This nonsense variant introduces a premature stop at codon 383, which is well upstream of the MSH2 codon 891 cutoff for very strong PVS1 evidence and is consistent with loss of function as an established disease mechanism for MSH2-related disease.

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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.23911e-06; MAF= 0.00012%, 2/1614058 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09823e-05; MAF= 0.00110%, 1/91056 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel).
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 = 0.09). BayesDel score = 0.66.
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; COSV51878760, n = 9 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR383
Hotspots ↗