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Schema Name MSH2 Schema for Lynch syndrome
Accession MS020700047.3
Gene(s) MSH2
Schema Caption Association of a truncating variant (rs63750245) in MSH2 gene with increased risk for Lynch syndrome.
Schema Description HGMD lists a large number (around 500) of germline mutations in this gene known to increase cancer risk, most commonly for a form of colon cancer (Lynch syndrome), but also endometrial and ovarian cancers. Many of these are truncation or direct hits on splice sites and so are expected to have a very high impact on protein function Penetrance of the mutations varies, with the most penetrant leading to close to 100% risk of cancer by middle age (Nagy et al. 2004). We seek to elucidate the mechanisms underlying this association. The exact mechanism may differ slightly for different mutations and we use the example of a likely highly penetrant nonsense mutation (Bartosova et al. 2003). Somatic mutations are also found in this gene for some cancers. The mechanism of action of those is not considered here. The rs63750245:C>T truncation base change in MSH2 is expected to lead to nonsense-mediated decay (NMD), decreasing mRNA abundance by half, and as a consequence, also decreasing protein abundance. As a result, all complexes of this protein will also be of reduced abundance. That affects two processes – DNA mismatch repair of both short and longer mismatch regions, and apoptosis triggered by recognition of drug-induced DNA damage. Reduction of the first of these processes will lead to greater accumulation of somatic mutations and microsatellite instability, and hence increased cancer risk. Reduction of apoptosis will lead to drug resistance of cancer cells.
Author(s) Kunal Kundu, Lipika R. Pal, Lindley Darden and John Moult
Curator(s) John Moult, Kunal Kundu
Last Modified Sun Jun 14 2020 01:37:39 GMT-0400 (Eastern Daylight Time)
Sub-state Perturbation (SSP) Annotations
Component ID: SSP1
Stage: DNA
SSP Class: SNV [HET]
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: rs63750245:C>T in MSH2
Confidence Score: 5
Comment:
For Evidence: PMID:12655568
Against Evidence:
Component ID: SSP2
Stage: RNA
SSP Class: SNV
Other SSP Class:
Modifier: NA
Ontology: SO
SSP Instance: NM_000251.2: c.1030C>T
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Component ID: SSP3
Stage: RNA
SSP Class: mRNA Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: NM_000251.2: c.1030C>T
Confidence Score: 4
Comment: The NMD has not been confirmed by any experiment and therefore the confidence score is 4.
For Evidence:
Against Evidence:
Component ID: SSP4
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: DNA mismatch repair protein Msh2
Confidence Score: 4
Comment:
For Evidence:
Against Evidence:
Component ID: SSP5
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology: ADMO
SSP Instance: MSH2-MSH6 (MutSα)
Confidence Score: 5
Comment: Binding of hMutSα to DNA mismatch sites arising from radiation damage and DNA polymerize errors. hMutSα preferentially identifies base-base mismatches and indels mispairs of 1 or 2 nucleotides by scanning dsDNA in the nucleus.
For Evidence: PMID:8942985, PMID:7604264
Against Evidence:
Component ID: SSP6
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology: ADMO
SSP Instance: MSH2-MSH3 (MutSβ)
Confidence Score: 5
Comment: Lower abundance of the hMSH2-hMSH3 protein complex, hMutSβ. The hMutSβ complex identifies larger indels mispairs by recognizing the topology of dsDNA i.e. bending of the DNA double helix (Gupta et al. 2011). Upon finding mispairs, both hMutSα and hMutSβ interact with MLH1 to repair the damaged DNA. PCNA interacts with MSH2 and MLH1 in the complexes and plays roles in the initiation and DNA resynthesis steps of MMR (Umar et al. 1996).
For Evidence: PMID:8942985, PMID:22179786, PMID:8858149
Against Evidence:
Component ID: SSP8
Stage: DNA
SSP Class: SNV
Other SSP Class:
Modifier: Increased
Ontology: SO
SSP Instance: Somatic single base mutations
Confidence Score: 5
Comment: Cells accumulate more single base and small indel somatic mutations because of the lower repair rate.
For Evidence: PMID:11048710, PMID:11048711, PMID:29731845
Against Evidence:
Component ID: SSP9
Stage: DNA
SSP Class: IN/DEL
Other SSP Class:
Modifier: Increased
Ontology: NCIT
SSP Instance: Small insertion / deletion
Confidence Score: 5
Comment:
For Evidence: PMID:11048710, PMID:11048711, PMID:29731845
Against Evidence:
Component ID: SSP10
Stage: DNA
SSP Class: IN/DEL
Other SSP Class:
Modifier: Increased
Ontology: NCIT
SSP Instance: Large insertion / deletion
Confidence Score: 5
Comment:
For Evidence: PMID:7479796
Against Evidence:
Component ID: SSP11
Stage: Cell
SSP Class: Other
Other SSP Class: Cancer Cell
Modifier: NA
Ontology:
SSP Instance: Drug resistant Hereditary Nonpolyposis Colorectal Cancer cell (HNPCC)
Confidence Score: 5
Comment:
For Evidence: PMID:15660526
Against Evidence:
Component ID: SSP7
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: Phosphorylated p53 and p73
Confidence Score: 5
Comment: The MMR-deficient cells fail to phosphorylate p53 and p73 in response to DNA damage. However, the exact mechanism by which the Mutsα induces phosphorylation is not known therefore the black oval.
For Evidence: PMID:18157157
Against Evidence:
Biomarker(s) Annotations
Component ID: BM1
Stage: DNA
SSP Class: Other
Other SSP Class: Hyper-mutable Phenotype
Modifier: NA
Ontology:
SSP Instance: Microsatellite instability
Confidence Score: 5
Comment: Lower repair rate for longer mismatch regions leads to microsatellite instability. Complex mutations in both MSH2 and MSH6 genes also caused hypermutated microsatellite.
For Evidence: PMID:28585546, PMID:20420947, PMID:20421420, PMID:25255306
Against Evidence:
Mechanism Module (MM) Annotations
Component ID: MM1
Mechanism Class Name: Transcription Rate
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Transcription
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Component ID: MM2
Mechanism Class Name: Nonsense Mediated Decay
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 4
Comment: Introduction of the nonsense codon relatively early in the message (codon 344 out of 934) is expected to lead to nonsense mediated decay
For Evidence:
Against Evidence:
Component ID: MM3
Mechanism Class Name: Translation
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Translation
Confidence Score: 4
Comment:
For Evidence:
Against Evidence:
Component ID: MM4
Mechanism Class Name: Le Chatelier
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: Reduced abundance of hMSH2 will lead to reduced abundance of complexes it participates in. There are two relevant complexes, hence the chain splits at this point.
For Evidence:
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: DNA mismatch repair
Modifer: Decreased
Ontology: GRO
Mechanism Instance: Decreased SNV & small IN/DEL repair
Confidence Score: 5
Comment: Less hMutSα mediated DNA mismatch repair. The lower coverage of mismatch sites by hMutSα must have this consequence. It is likely that the system is very sensitive to small decreases in repair efficiency, but again, no direct evidence.
For Evidence: PMID: 23572416
Against Evidence:
Component ID: MM7
Mechanism Class Name:
Other Mechanism Class Name: DNA mismatch repair
Modifer: Decreased
Ontology: GRO
Mechanism Instance: Decreased large IN/DEL repair
Confidence Score: 5
Comment: Less hMutSβ mediated DNA mismatch repair. The lower coverage of mismatch sites by hMutSβ must have this consequence. It is likely that the system is very sensitive to small decreases in repair efficiency, but again, no direct evidence.
For Evidence: PMID:21960445
Against Evidence:
Component ID: MM10
Mechanism Class Name: activity of oncogene / tumor suppressor genes
Other Mechanism Class Name:
Modifer: Altered
Ontology:
Mechanism Instance: Altered activity of oncogene / tumor suppressor genes
Confidence Score: 5
Comment: Higher probability of one or more cell being transformed into cancer cells because of alteration in the regulations of cancer related gene expression and their translation.
For Evidence: PMID:24196629
Against Evidence:
Component ID: MM8
Mechanism Class Name:
Other Mechanism Class Name: Cell cycle arrest / apoptosis
Modifer: Altered
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Component ID: MM9
Mechanism Class Name: Accumulation of IN/DEL
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Accumulation of IN/DELs
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Component ID: MM5
Comment:
For Evidence:
Against Evidence:
Environmental Factor Annotations
Therapeutic Interventions Annotations