MSH6 c.3261dup, p.Phe1088LeufsTer5
NM_000179.3:c.3261dup
COSMIC ID: COSM308681
Pathogenic
This frameshift variant in MSH6 introduces a premature stop codon well before codon 1341 (PVS1_Very Strong) and is reported as pathogenic by multiple reputable sources (PP5_Supporting). No benign or contradictory evidence is available. According to VCEP rules, PVS1 plus any additional criterion yields a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PP5
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.3261dup
Protein Change
F1088Lfs*5
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
Alternate Identifiers
COSM308681
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.3261dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00605%
Rare
Highest in Population
Remaining individuals
0.0279%
Low Frequency
Global: 0.00605%
Remaining individuals: 0.0279%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 280876Alt: 17Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00605%, 17/280876 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0279%, 2/7178 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
15 publications
Likely Pathogenic
Based on 44 submitter reviews in ClinVar
Submitter Breakdown
42 Path
2 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (15)
Variant summary: The MSH6 c.3261dupC (p.Phe1088Leufs) variant is located in exon 5 and results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was observed in a large, broad control population, ExAC, with an allele frequency of 211/120336 (1/570), which is approximately 12 times the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7031. The high prevalence of the variant in controls can be explained by possibility of sequencing error, although the low penetrance is possibility too. The reason for low penetrance could be the existence of alternative splice acceptor site 7bp downstream of duplicated base, which can result in alternative protein lacking 32 amino acids. The variant of interest has been reported in multiple affected individuals with varying phenotypes, Lynch syndrome, atypical HNPCC, HNPCC (fulfilling either Bethesda or Amsterdam criteria), along with a family that had three homozygous children diagnosed with constitutional mismatch repair deficiency syndrome. In addition, one family (Palmer_2010) did indicate a lack of co-segregation with disease, along with another study, Yurgelun_2015 indicating the variant to have co-occurred with another pathogenic STK11 variant, c.375-1C>T. While other publications did indicate the variant segregated with disease (Akiyama_1997 and Ollikinen_2005). Furthermore, multiple reputable databases/clinical laboratories and publications cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Likely Pathogenic.
PP1, PP4, PP5, PS4_moderate, PVS1
Clinical Statement
This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Pathogenic (42 clinical laboratories) and as pathogenic (1 clinical laboratories) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel.
Expert Panel Reviews
Pathogenic
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
COSMIC ID
COSM308681
Recurrence
85 occurrences
PM1 Criteria
Applied
Criterion PM1 is applied based on the high recurrence in COSMIC database.
COSMIC Database Preview
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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 F1088Lfs*5 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, 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: NM_000179.3:c.3261dup results in a frameshift and premature stop (F1088Lfs*5), generating a PTC before codon 1341. Therefore, this criterion is applied at Very Strong strength because the variant introduces a truncating alteration predicted to undergo NMD in a gene where loss‐of‐function is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established 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 standard ACMG guidelines, the rule for PS2 is: "Confirmed de novo (both maternity and paternity) in a patient with the disease and no family history". The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well‐established functional studies show a deleterious effect". The evidence for this variant shows: no functional assay data are available demonstrating impact on MSH6 function. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls". The evidence for this variant shows: no case‐control or enrichment data have been provided. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is not defined for MSH6. Standard ACMG defines PM1 as: "Located in a mutational hot spot and/or critical functional domain without benign variation". The evidence for this variant shows: frameshift outside any defined hot spot or critical domain annotation. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4". The evidence for this variant shows: MAF = 0.00605% (≈1 in 1,650), which exceeds the threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder". The evidence for this variant shows: no recessive inheritance or trans data available. 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 indels or stop-loss variants". The evidence for this variant shows: it is an out-of-frame duplication causing a frameshift, not an in-frame alteration. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 (Moderate) is: "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 variant, 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, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no 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 low rate of benign missense variation". The evidence for this variant shows: it is a frameshift, 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: no consensus pathogenic in silico predictions and SpliceAI score is low (0.07). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 (Supporting) is: "1 CRC/Endometrial MSI-H tumor or loss of MMR protein consistent with gene location". The evidence for this variant shows: no tumor or IHC data. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but evidence is not available for independent evaluation". The evidence for this variant shows: ClinVar contains multiple reports of Pathogenic/Likely Pathogenic by clinical labs and expert panels. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Allele frequency ≥0.22% in gnomAD v4". The evidence for this variant shows: MAF = 0.00605%, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Allele frequency ≥0.022% and <0.22% in gnomAD v4". The evidence for this variant shows: MAF = 0.00605%, below threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Co-occurrence in trans with a known pathogenic variant in LS cancer patient without CMMRD". The evidence for this variant shows: no such co-occurrence data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well‐established functional studies show no damaging effect". The evidence for this variant shows: no functional assays demonstrating benign effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". 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 a gene where only truncating variants are pathogenic". The evidence for this variant shows: it is truncating, not missense. 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 for a dominant gene". The evidence for this variant shows: no such 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 a repetitive region without known function". The evidence for this variant shows: it is out-of-frame. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence support no impact on gene or gene product". The evidence for this variant shows: not a missense/splice variant and no benign computational data. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such data. 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, but evidence not available". The evidence for this variant shows: no benign assertions. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous or intronic variant with no expected impact on splicing". The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.