Genetic Information

Gene & Transcript Details

Gene
MSH6
Transcript
NM_000179.3 MANE Select
Total Exons
—
Reference Sequence
NC_000002.11
Alternative Transcripts
IDStatusDetails
NM_000179.2 RefSeq Select 4435 nt | 153–4235
NM_000179.1 Alternative 4264 nt | 88–4170
NM_000179.3 MANE Select 4265 nt | 90–4172

Variant Details

HGVS Notation
NM_000179.3:c.3556+1G>C
Protein Change
Splice
Location
Exon 6 (Exon 6 of )
6
5'Exon Structure3'
Functional Consequence
Loss of Function
Alternate Identifiers
—

Clinical & Population Data

Population Frequency

gnomAD
Global Frequency
0.0 in 100,000
Extremely Rare
ACMG Criteria Applied PM2
This variant is absent or extremely rare in population databases (PM2 criteria applies).

ClinVar

Open
Classification
Pathogenic
1 publications
Publications List
PMID: 26436112

This sequence change affects a donor splice site in intron 6 of the MSH6 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Lynch syndrome (PMID: 26436112; Invitae). ClinVar contains an entry for this variant (Variation ID: 572617). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Clinical Statement

"This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories)."

COSMIC Somatic Evidence

Open
COSMIC ID
Recurrence
0 occurrences
PM1 Criteria
Not Applied
COSMIC Database Preview
COSMIC Preview
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Functional Impact & Domains

Functional Domain

Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain.
Related Variants in This Domain
No evidence of other pathogenic variants at this position in gene MSH6.

Functional Studies & Therapeutic Relevance

Functional Summary

Error in OpenAI Consolidation. OncoKB: MSH6SpliceMSH6SpliceSomaticNCBI Gene:2956|Show additional gene information Variant OverviewMSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.The MSH6 splice alteration has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown. JAX-CKB: No results found

Database Previews
OncoKB
OncoKB Preview
JAX-CKB
JAX-CKB Preview

Click on previews to view full database entries. External databases may require institutional access.

Computational Analysis

Pathogenicity Predictions

SpliceAI
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
REVEL Score
0.0
Threshold: ≥0.75 = PP3 applied

SpliceAI Scores

Window: ±500bp
Effect Type Score Position
- Acceptor Loss (AL) 0.95 -118 bp
- Donor Loss (DL) 1.0 -1 bp
+ Acceptor Gain (AG) 0.0 179 bp
+ Donor Gain (DG) 0.0 246 bp
High impact (≥0.5) Medium impact (0.2-0.49) Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)

Filter Criteria:
PVS1

PVS1 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PM2

PM2 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PP3

PP3 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

PP5

PP5 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)