PVS1_Very_Strong: NM_000179.3:c.1135_1139del introduces a premature termination codon at p.Arg379Ter, well within the VCEP boundary of codon 1341. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome.1 PM2_Supporting: This variant is extremely rare in population databases. In gnomAD v4.1, allele frequency is 2.48e-06 (4/1,614,148 alleles, grpmax FAF=7.9e-07), below the VCEP threshold of <0.00002.2 PP4_Moderate: The variant has been observed in a patient with two independent MSH6-deficient tumors (endometrial cancer at age 54 and colorectal cancer at age 58), meeting VCEP criteria for 2 independent tumors with IHC loss consistent with the variant gene. PS2_Supporting: The variant was identified as a likely de novo mosaic variant detectable across all three germ layers in a patient with MSH6-deficient Lynch spectrum tumors, meeting 0.5 de novo points under the VCEP PS2 scoring system. Combining 1 Very Strong (PVS1) + 2 Supporting (PM2 + PS2) satisfies VCEP Rule 4 (1 VS + >=2 Sup → Pathogenic). The additional Moderate criterion (PP4) further supports the pathogenic classification.3
MSH6
Final classification
Pathogenic
MSH6 c.1135_1139del · p.Arg379Ter
MSH6
PVS1_Very_Strong: NM_000179.3:c.1135_1139del introduces a premature termination codon at p.Arg379Ter, well within the VCEP boundary of codon 1341. Loss of function is an established disease mechanism for MSH6 in Lynch syndrome.
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PS2 supporting, PM2 supporting, PP4 moderate, PP5 supporting; maps to Pathogenic.
Classification rationale
PVS1PS2PM2PP4PP5
Pathogenic
MSH6 c.1135_1139del
PVS1 + PS2 + PM2 + PP4 + PP5
→
Pathogenic
Gene diagram
· NM_000179.3 · variants mapped to exon structure
MSH6
NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 5 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
4 / 1,614,148
0.00025%
Highest · European (non-Finnish)
0.00034%
Homozygotes
0
grpmax FAF
7.9e-05%
Allele frequency by ancestry — gnomAD v4.1
observed in 1 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 4 / 1,180,022 | 0.00034% | 0 |
| Admixed American | 0 / 60,026 | — | — |
| European (Finnish) | 0 / 64,030 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,890 | — | — |
| Middle Eastern | 0 / 6,062 | — | — |
| South Asian | 0 / 91,080 | — | — |
| Ashkenazi Jewish | 0 / 29,606 | — | — |
| African/African American | 0 / 75,020 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 2.47809e-06; MAF= 0.00025%, 4/1614148 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38977e-06; MAF= 0.00034%, 4/1180022 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
Overall AF
1 / 250,986
0.0004%
Highest · European (non-Finnish)
0.00088%
Homozygotes
0
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 1 / 113,328 | 0.00088% | 0 |
| African/African American | 0 / 16,248 | — | — |
| Admixed American | 0 / 34,572 | — | — |
| Ashkenazi Jewish | 0 / 10,066 | — | — |
| East Asian | 0 / 18,394 | — | — |
| European (Finnish) | 0 / 21,644 | — | — |
| Remaining individuals | 0 / 6,118 | — | — |
| South Asian | 0 / 30,616 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 3.98429e-06; MAF= 0.00040%, 1/250986 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82394e-06; MAF= 0.00088%, 1/113328 alleles, homozygotes = 0).
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Pathogenic (20 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89174)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 30 PMIDs triaged · 8 high-priority
30papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
24362816 ↗
functional
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated g
BS3PM1PS3
1651234 ↗
functional
Altering the conserved nucleotide binding motif in the Salmonella typhimurium MutS mismatch repair protein affects both its ATPase and mismatch binding activities.
The Salmonella typhimurium and Escherichia coli MutS protein is one of several methyl-directed mismatch repair proteins that act together to correct replication errors. MutS is homologous to the Streptococcus pneumoniae HexA mismatch repair protein and to the Duc1 and Rep1 proteins of human and mouse. Homology between the deduced amino acid sequence of both MutS and HexA, and the type A nucleotide
BS3PM1PS3
22810696 ↗
functional
Comprehensive molecular characterization of human colon and rectal cancer.
To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of the
BS3PM1PS3
24362816 ↗
functional
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated g
BS3PP5PS3PS4
24755471 ↗
functional
Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.
Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, re
BS3PM1PS3
9111312 ↗
functional
Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition.
Recent studies have shown that Saccharomyces cerevisiae Msh2p and Msh6p form a complex that specifically binds to DNA containing base pair mismatches. In this study, we performed a genetic and biochemical analysis of the Msh2p-Msh6p complex by introducing point mutations in the ATP binding and putative helix-turn-helix domains of MSH2. The effects of these mutations were analyzed genetically by me
BS3PM1PS3
9564049 ↗
functional
hMSH2 and hMSH6 play distinct roles in mismatch binding and contribute differently to the ATPase activity of hMutSalpha.
In extracts of human cells, base-base mismatches and small insertion/deletion loops are bound primarily by hMutSalpha, a heterodimer of hMSH2 and hMSH6 (also known as GTBP or p160). Recombinant hMutSalpha bound a G/T mismatch-containing oligonucleotide with an apparent dissociation constant Kd = 2.6 nM, while its affinity for a homoduplex substrate was >20-fold lower. In the presence of ATP, hM
BS3PM1PS3
9822680 ↗
functional
Nucleotide-promoted release of hMutSalpha from heteroduplex DNA is consistent with an ATP-dependent translocation mechanism.
ATP hydrolysis by bacterial and eukaryotic MutS activities is required for their function in mismatch correction, and two different models for the role of ATP in MutS function have been proposed. In the translocation model, based on study of bacterial MutS, ATP binding reduces affinity of the protein for a mismatch and activates secondary DNA binding sites that are subsequently used for movement o
BS3PM1PS3
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links