MSH6 c.315G>A, p.Trp105Ter
NM_000179.3:c.315G>A
Pathogenic
MSH6 c.315G>A (p.W105*) introduces a premature stop codon resulting in a truncated protein with demonstrated mismatch repair defect, is absent from population databases, and is reported as pathogenic by a reputable source. Applying PVS1 (Very Strong), PS3 (Moderate), PM2 (Supporting), and PP5 (Supporting) yields a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.315G>A
Protein Change
W105*
Location
Exon 2
(Exon 2 of 10)
5'Exon Structure (10 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000179.3
Genome Browser
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HGVS InputNM_000179:c.315G>A
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
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 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
Functional Summary
The MSH6 W105* variant is a truncating mutation that results in a premature stop codon, leading to a C-terminally truncated protein. This truncation causes the loss of part or all of the highly conserved MutS domain, resulting in impaired ATPase activity, DNA binding, and mismatch repair. Such defects are associated with microsatellite instability and hypermutation, particularly in colorectal and endometrial cancers. Therefore, the functional evidence supports a damaging effect of this variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Neutral: Show all
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: c.315G>A (p.W105*) introduces a premature stop codon at codon 105, well before codon 1341, predicted to undergo nonsense-mediated decay. Therefore, this criterion is applied at Very Strong strength because it is a truncating variant in a gene where loss of function is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG 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 nonsense change, not a missense. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo confirmation data. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 Moderate Strength is: "MMR function defect following functional assay flowchart*." The evidence for this variant shows: W105* leads to C-terminal truncation of MSH6, loss of ATPase activity, DNA binding and mismatch repair in functional studies. Therefore, this criterion is applied at Moderate strength because well-established functional assays demonstrate a mismatch repair defect.
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 with the prevalence in controls." The evidence for this variant shows: no case-control or familial aggregation 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 and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: no evidence that codon 105 lies in a defined mutational hotspot beyond general truncation. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 Supporting Strength is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: not present in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no data on trans configuration in a recessive context. 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 a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a nonsense variant resulting in truncation, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: it is a nonsense change, not a missense substitution. 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 data. 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 in a gene definitively known to cause the disease." 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 that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: it is a nonsense 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 on the gene or gene product." The evidence for this variant shows: computational tools are inconclusive and variant is a truncation. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no detailed phenotype or tumor data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar lists this variant as Pathogenic by one clinical laboratory without accessible primary evidence. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in population databases." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder." The evidence for this variant shows: absent (MAF = 0%). Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder, with full penetrance expected at an early age." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: functional studies demonstrate damaging 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 members of a family." 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 for which primarily truncating variants are known to cause disease." The evidence for this variant shows: this is a truncating variant, not a 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 recessive disorder." 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 deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is a nonsense variant, not an in-frame indel. 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 suggest no impact on gene or gene product." The evidence for this variant shows: computational predictions are mixed and variant is a truncation. 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 recently reports variant as benign, but evidence is not available." The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "A synonymous variant for which splicing prediction algorithms predict no impact." The evidence for this variant shows: it is a nonsense variant, not synonymous. Therefore, this criterion is not applied.