Starting

Initialising…

MSH2

Final classification

Uncertain Significance

MSH2 c.802dup · p.Ser268PhefsTer16

MSH2

The MSH2 c.802dup (p.(Ser268PhefsTer16)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic by 1 clinical laboratory.

Gene

MSH2

Transcript

NM_000251.3

HGVS · transcript:coding

NM_000251.3:c.802dup

Consequence

N/A

GRCh38

chr2:47414275 G>GT

GRCh37

chr2:47641414 G>GT

Basis Applied the explicit InSiGHT/CSPEC final-classification framework from final_classification_framework.json (source: cspec_ruleset; Richards et al. 2015 combining rules as represented in the retrieved CSPEC ruleset), rather than generic ACMG fallback rules. ▾

Applied the explicit InSiGHT/CSPEC final-classification framework from final_classification_framework.json (source: cspec_ruleset; Richards et al. 2015 combining rules as represented in the retrieved CSPEC ruleset), rather than generic ACMG fallback rules.

Classification rationale

PM2PVS1 Uncertain Significance

MSH2 c.802dup

The MSH2 c.802dup (p.(Ser268PhefsTer16)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic by 1 clinical laboratory.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the MSH2 PM2 threshold of <0.00002 (<1 in 50,000 alleles).² The duplication causes a frameshift with a premature stop codon at p.(Ser268PhefsTer16), and this truncation is upstream of the MSH2 codon 891 cutoff for PVS1 Very Strong in the InSiGHT specification.³ SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, indicating no additional splice effect is predicted beyond the truncating consequence of the duplication.⁴

PM2 + PVS1 → Uncertain Significance

1 cosmic ↗clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 cspec ↗pvs1_gene_contextpvs1_variant_assessment

4 spliceai ↗

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

MSH2 NM_000251.3

Fetching transcript structure from UCSC…

Applied criteria · 2 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

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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