MSH6 c.3263del, p.Phe1088SerfsTer2
NM_000179.3:c.3263del
Pathogenic
The MSH6 c.3263delT variant introduces a premature stop codon at codon 1089 (PVS1 Very Strong) and is absent from population databases (PM2 Supporting). These combined criteria support a classification of Likely Pathogenic.
ACMG/AMP Criteria Applied
PVS1
PM2
Genetic Information
Gene & Transcript Details
Gene
MSH6
Transcript
NM_000179.3
MANE Select
Total Exons
10
Strand
Forward (+)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000179.2 | RefSeq Select | 10 exons | Forward |
| NM_000179.1 | Alternative | 10 exons | Forward |
Variant Details
HGVS Notation
NM_000179.3:c.3263del
Protein Change
F1088Sfs*2
Location
Exon 5
(Exon 5 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 1088: F1088L
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.3263del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change creates a premature translational stop signal (p.Phe1088Serfs*2) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colon cancer (PMID: 15872200). ClinVar contains an entry for this variant (Variation ID: 1729560). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 1088: F1088L
PM5 criterion applied.
Functional Summary
The MSH6 F1088Sfs*2 variant results in a frameshift and premature truncation of the MSH6 protein. However, this variant has not been functionally characterized to determine its specific impact on protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines for MSH6, the rule for PVS1 is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 1341 in MSH6." The evidence for this variant shows: c.3263delT (F1088Sfs*2) introduces a premature stop at codon 1089, well before codon 1341, in a gene where loss‐of‐function is a known mechanism. Therefore, this criterion is applied at Very Strong strength because the variant is a truncating frameshift predicted to undergo NMD.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic." The evidence for this variant shows: it is a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong ≥4 de novo points; Strong 2-3 de novo points; Moderate 1 de novo point." The evidence for this variant shows: no de novo inheritance data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong Calibrated functional assays with functional odds for Pathogenicity >18.7." The evidence for this variant shows: no functional assay data are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared to controls." The evidence for this variant shows: no case-control or statistical enrichment data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or critical functional domain without benign variation." The evidence for this variant shows: no known mutational hotspot or critical domain annotation. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for MSH6, the rule for PM2 is: "Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: MAF=0% in gnomAD v4. Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Used for recessive disorders with detection of variant in trans with pathogenic variant." The evidence for this variant shows: MSH6-associated Lynch syndrome is autosomal dominant and no trans data. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat region." The evidence for this variant shows: it is a frameshift variant, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for PM5 is: "Moderate Missense change at an amino acid residue where a different missense change was classified as Pathogenic." The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for PP1 is: "Supporting/Moderate/Strong co-segregation with disease depending on Bayes likelihood ratio." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation." The evidence for this variant shows: it is a frameshift variant, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect." The evidence for this variant shows: SpliceAI score 0.05 indicates no significant splicing impact, and the variant is a frameshift LOF. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for PP4 is: "Supporting/Moderate/Strong tumor phenotype data (MSI-H and loss of MMR) depending on number of tumors." The evidence for this variant shows: no tumor phenotype data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The evidence for this variant shows: reported as pathogenic in ClinVar, but PP5 is deprecated and not recommended. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BA1 is: "Stand Alone GnomAD v4 Grpmax filtering allele frequency ≥0.0022." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BS1 is: "Strong GnomAD v4 Grpmax filtering allele frequency ≥0.00022 and <0.0022." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BS2 is: "Strong co-occurrence in trans with known pathogenic variant without CMMRD evidence." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BS3 is: "Strong calibrated functional assays with odds ≤0.05 OR synonymous/intronic without mRNA aberration." The evidence for this variant shows: no functional assay data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BS4 is: "Strong lack of co-segregation (Bayes LR <0.05)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in gene where only LOF causes disease." The evidence for this variant shows: it is a frameshift LOF variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in a dominant gene." The evidence for this variant shows: no trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in repetitive region without known function." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BP4 is: "Supporting for intronic/synonymous variants if SpliceAI ≤0.1 indicating no splicing impact." The evidence for this variant shows: it is a frameshift variant and splicing predictions are not relevant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BP5 is: "Tumors with alternate cause inconsistent with LS MMR deficiency." The evidence for this variant shows: no data on alternate causes in cases. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows: no such benign report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for MSH6, the rule for BP7 is: "Supporting for synonymous/intronic variants at or beyond -21/+7 with no splicing impact." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.