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LYFE SCIENCES
Project: HERA
NM_000251.3:c.942+3A>G
p.?  ·  MSH2
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Classification rationale
1

The MSH2 c.942+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with predominantly likely pathogenic submissions, although some submissions classify it as uncertain significance.

clinvar ↗
2

This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 3/11,582 alleles (total AF 0.00025902) with grpmax FAF 0.00004967, which is above the MSH2 VCEP PM2 threshold of less than 0.00002 and below the BS1 threshold of at least 0.0001.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

Published RNA studies reported that this variant disrupts MSH2 donor splicing and generates an exon 5-skipped transcript, supporting a true splice defect despite its non-canonical +3 position.

PMID:10978353 ↗ PMID:16395668 ↗
4

SpliceAI predicts a low splice effect with a maximum delta score of 0.02, which is below the MSH2 VCEP PP3 threshold of at least 0.2 and within the BP4 threshold of 0.1 or less, but this in silico result is inconsistent with the published RNA evidence.

spliceai ↗ cspec ↗ PMID:10978353 ↗ PMID:16395668 ↗
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 v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0.000259023; MAF= 0.02590%, 3/11582 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00225225; MAF= 0.22523%, 1/444 alleles, homozygotes = 0); grpmax FAF= 4.967e-05.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (5 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as likely pathogenic (1 clinical laboratory).
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 = 0.02).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
06
Cancer hotspots
No cancer hotspot summary recorded.