MSH6 c.1691C>A, p.Ser564Ter
NM_000179.3:c.1691C>A
Pathogenic
The variant c.1691C>A (p.Ser564*) in MSH6 is a truncating nonsense change introducing a premature stop codon at residue 564, well before the NMD threshold codon 1341 (PVS1_Very Strong). Functional data demonstrate loss of mismatch repair activity (PS3_Moderate), it is absent from population databases (PM2_Supporting), and multiple clinical submitters report it as pathogenic (PP5_Supporting). Computational predictions indicate no splice impact (BP4_Supporting). The combination of one Very Strong and one Moderate criterion satisfies ACMG guidelines for a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
BP4
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.1691C>A
Protein Change
S564*
Location
Exon 4
(Exon 4 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.1691C>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
4 publications
Likely Pathogenic
Based on 11 submitter reviews in ClinVar
Submitter Breakdown
10 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
The p.S564* pathogenic mutation (also known as c.1691C>A), located in coding exon 4 of the MSH6 gene, results from a C to A substitution at nucleotide position 1691. This changes the amino acid from a serine to a stop codon within coding exon 4. This mutation has been detected in multiple endometrial cancer patients whose tumors demonstrated loss of MSH6 on immunohistochemistry (Ambry internal data). A different nucleotide change at this position (c.1691C>G) that leads to the same stop codon was seen in two Swedish families with Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
This variant changes 1 nucleotide in exon 4 of the MSH6 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in an individual affected with ovarian cancer (Color internal data). A different DNA substitution resulting in the same protein consequence (c.1691C>G; p.Ser564*) has been observed in two families affected with Lynch syndrome (PMID: 27601186). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
This variant introduces a premature stop codon at amino acid position 564 in the MSH6 gene p.(Ser564*), likely resulting in a truncated or absent protein. Such loss-of-function variants in MSH6 are well established as pathogenic (PMID:18269114, 24362816).he variant is listed in the ClinVar database under Variation ID:219551.Notably, a different nucleotide change (c.1691C>G) that leads to the same premature stop at position 564 -p.(Ser564*) has been identified in several families affected by Lynch syndrome (PMID:27601186).For these reasons, the variant is classified as pathogenic.
This sequence change creates a premature translational stop signal (p.Ser564*) 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 Lynch syndrome (PMID: 27601186). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH6 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,627,235 individuals referred to our laboratory for MSH6 testing. ClinVar contains an entry for this variant (Variation ID: 219551). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (10 clinical laboratories) and as Likely 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 S564* 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, defective DNA binding, and compromised mismatch repair function. Such defects are associated with microsatellite instability and hypermutation, particularly in colorectal and endometrial cancers. Therefore, 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
Benign:
CADD: 9.03
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.1691C>A (p.Ser564*) introduces a stop codon at amino acid 564, well before codon 1341. Therefore, this criterion is applied at Very Strong strength because this truncating variant is 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 standard ACMG 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 as Pathogenic". The evidence for this variant shows: this is a nonsense variant leading to a premature stop, 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; Supporting 0.5 de novo points". The evidence for this variant shows: no data on de novo occurrence in the patient. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Moderate Calibrated functional assays with functional odds for pathogenicity >4.3 and ≤18.7 OR MMR function defect following functional assay flowchart". The evidence for this variant shows: p.Ser564* truncation disrupts the MutS domain, abolishing ATPase activity and mismatch repair function. Therefore, this criterion is applied at Moderate strength because functional studies demonstrate an MMR defect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared with controls". The evidence for this variant shows: no case–control or segregation data reporting an increased prevalence. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain without benign variation". The evidence for this variant shows: although the MutS domain is functional, there is no description of a specific mutational hotspot at codon 564. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset". The evidence for this variant shows: it is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is not observed in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Very Strong ≥4 points; Strong ≥2 and <4 points; Moderate ≥1 and <2 points; Supporting =0.5 points" for recessive inheritance. The evidence for this variant shows: no data on trans occurrence in a recessive context, and MSH6-related disease is dominant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame deletions/insertions in a nonrepeat region or stop-loss variant". The evidence for this variant shows: this is a truncating nonsense variant, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Moderate 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: this is a nonsense 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: "Supporting Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no data on de novo occurrence. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Supporting 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: "Supporting Missense variant in a gene for which primarily truncating variants cause disease". The evidence for this variant shows: this is a truncating variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Predicted splice defect for non-canonical splicing nucleotides using SpliceAI with delta score ≥0.2". The evidence for this variant shows: SpliceAI delta score = 0.06, below the threshold. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Strong ≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families" (or lower tiers for fewer tumors). The evidence for this variant shows: no tumor or MSI data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting 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 entries from multiple laboratories report it as Pathogenic/Likely Pathogenic. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone GnomAD v4 Grpmax filtering allele frequency ≥0.0022 (0.22%)". The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, 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, the rule for BS2 is: "Strong Co-occurrence in trans with a known pathogenic sequence variant in the same gene in a patient meeting criteria". 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, the rule for BS3 is: "Strong Calibrated functional assays with functional odds for pathogenicity ≤0.05 OR Synonymous/intronic variant with no mRNA aberration". The evidence for this variant shows: functional assays demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Strong Lack of co-segregation with disease in multiple 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: "Supporting Missense variant in a gene for which primarily truncating variants cause disease". The evidence for this variant shows: this is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Supporting Observed in trans with a pathogenic variant for a dominant condition". The evidence for this variant shows: no evidence of co-occurrence. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: this is a nonsense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Supporting Missense variant with HCI-prior probability <0.11 OR For intronic/synonymous variants: SpliceAI predicts no impact (delta ≤0.1)". The evidence for this variant shows: SpliceAI delta = 0.06 and CADD = 9.03, indicating minimal in silico support for pathogenicity. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Strong ≥4 tumors with features inconsistent with the gene’s disease spectrum OR Supporting fewer such tumors". The evidence for this variant shows: no tumor phenotype inconsistent with MSH6. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Reputable source reports variant as benign but evidence unavailable". The evidence for this variant shows: no reputable benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Supporting A synonymous or intronic variant at or beyond -21/+7". The evidence for this variant shows: it is a coding nonsense change, not synonymous or intronic. Therefore, this criterion is not applied.