Starting

Initialising…

MSH2

Final classification

Pathogenic

MSH2 c.1147C>T · p.Arg383Ter

MSH2

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.

Gene

MSH2

Transcript

NM_000251.3

HGVS · transcript:coding

NM_000251.3:c.1147C>T

Consequence

N/A

GRCh38

chr2:47429812 C>T

GRCh37

chr2:47656951 C>T

Basis Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; maps to Pathogenic. ▾

Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; maps to Pathogenic.

Classification rationale

PVS1PM2PP5 Pathogenic

MSH2 c.1147C>T

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.¹ 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 0.00002.² 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.³

PVS1 + PM2 + PP5 → Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_decisiontree_mmr

Gene diagram · NM_000251.3 · variants mapped to exon structure

MSH2 NM_000251.3

Fetching transcript structure from UCSC…

Applied criteria · 3 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This 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).

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00012% · 2 / 1,614,058
0 hom

South Asian 1 / 91,056	0.0011%
European (non-Finnish) 1 / 1,180,020	8.5e-05%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

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 ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). BayesDel score = 0.66.

SpliceAI ↗

Functional 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 ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

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).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots