MSH2

Gene Facts

• HGNC Symbol: MSH2 (HGNC:7325)
• HGNC Name: mutS homolog 2
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: COCA1
• Alias symbols: HNPCC, HNPCC1, MSH-2
• %HI: 1.57
• pLI: 0
• LOEUF: 0.67
• Cytoband: 2p21-p16.3
• Genomic Coordinates:

  GRCh37/hg19:	chr2:47630206-47710367
  GRCh38/hg38:	chr2:47403067-47709830

• MANE Select Transcript: NM_000251.3 ENST00000233146.7
• Function: Component of the post-replicative DNA mismatch repair system (MMR). Forms two different heterodimers: MutS alpha (MSH2-MSH6 heterodimer) and MutS beta (MSH2-MSH3 heterodimer) which binds to DNA mismatches thereby initiating DNA repair. When bound, heterodimers bend the DNA helix and shields approximately 20 base pairs. MutS alpha recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. MutS beta recognizes larger insertion-deletion loops up to 13 nucleotides ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-35336
• ClinGen Curation ID: CCID:007483
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Assoc. with Reduced Penetrance: Yes
  Penetrance for MSH2 is gender specific, with no difference noted in penetrance between truncating and missense/aberrant splicing pathogenic variants (PMID: 34203177) Resources: See Lynch Syndrome Genereviews chapter (link above) UWash Analyze my Variant MSH2 page: http://analyze.myvariant.org/msh2-info PMID: 16083698, 19622357
• Last Evaluated: 10/13/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Lynch Syndrome

HI Evidence

• PUBMED: 10850409
  Germline variants within the MSH2 gene at 2p15 ( mismatch repair gene) have been seen in families Hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC is an autosomal dominant disease characterized clinically by increased risk of early development of colorectal cancer as well as increased risk for other tumors. Charbonnier et al. analyzed a cohort of of families with Amsterdam criteria positive (AC+) fHNPCC and Amsterdam criteria negative (AC-) HNPCC. A total of 12 genomic rearrangements and 12 point variants were detected in the MSH2 gene (4 frameshift, 4 nonsense, 1 splice site, 2 missense). One of the genomic rearrangements is a previously reported paracentric inversion of chromosome 2 (PMID 12203789). The remainder were exonic deletions of various lengths. The author also described a family that was negative for variants within the MSH2 gene and other MisMatch Repair (MMR) genes that had classical HNPCC and showed a high microsatellite instability phenotype and loss of MSH2 protein expression by IHC indicating the functional impairment of MSH2. Additional articles showing intragenic deletions include PMID 15949572, 9843200
• PUBMED: 12203789
  Wagner et al. describe a family with HNPCC (also known as Lynch syndrome) with a ~10 MB paracentric inversion that included exons 8-16 of the MSH2 gene. Inverse PCR showed the paracentric inversion breakpoints mapped within intron 7 and to a contig 10 Mb 3' of the MSH2 gene. Expression analysis was performed by a conversion analysis model which takes an MSH2 deficient rodent cellular background and using the patients lymphocytes to generate a somatic cell hybrid, analyzed the expression of the abnormal inverted MSH2 allele. Northern and Western blot analysis of the hybrid containing the abnormal inverted MSH2 show no detectable MSH2 mRNA or MSH2 protein, whereas the full length MSH2 allele was detected in the wild type allele hybrid.
• PUBMED: 9843200
  Wijnen et al. discussed the frequency of genomic deletion in HNPCC. A total of 137 families (51 Amsterdam criteria positive HNPCC and 86 Amsterdam negative with familial clustering of colorectal cancer reminiscent of HNPCC) were investigated by southern blot. Eight patients had aberrant restriction fragments indicating the presence of a genomic rearrangement. Four had aberrant restriction fragments indicative of an intragenic deletion in MSH2 encompassing various exons and a few of the deletions were confirmed by RT-PCR of the affected individuals. Author suggest that current technologies may not be able to detect all forms of variants including genomic deletions (including complete gene deletions) and rearrangements and that mutation analysis of the MSH2 gene should include the examination of its genomic structure by Southern blot.
• PUBMED: 34203177
  Dominguez-Valentin et al. used the InSiGHT database (https://www.insight-group.org/variants/databases/, accessed February 2021), to analyze 3000 different pathogenic or likely pathogenic (class 5 or 4 and, therefore, clinically actionable) germline sequence variants, of which 34% in MSH2, most affecting MSH2 are nonsense, frameshift, or splice site changes, which can be considered a priori to be pathogenic.
• PUBMED: 30710526
  Conner et al. analyzed a large cohort of 5,943 individuals with personal and/or family history of cancer. Of those, 2% carried a reportable MSH2 variant (PV or VUS), of which 0.7% were exonic duplications. RNA-Seq (with Tandem RT-PCR and cDNA Sanger sequencing confirm abnormal transcripts from RNA-Seq) to demonstrate that duplications in tandem, resulting in out-of-frame transcripts containing the duplicated exons which led to LoF and the Lynch phenotype with colorectal cancer.

• HI Evidence Comments: Although there have been no publications based on complete loss of the gene (hemizygous gene), there have been several reports of interstitial deletions, inversions, and point mutations (missense, framshift, nonsense) described in the literature that represent and autosomal dominant inheritance pattern. Functional studies have shown that deletions or disruptions result in a loss of function (inactivating mutations) (12203789, 9843200). Intragenic duplications have also been associated with HNPCC; these duplications may cause disease through a loss of function mechanism. Charbonnier et al. (PMID:10850409) detected two intragenic duplications of the MSH2 gene within 19 HNPCC families previously analyzed using classical methods did not identify any alterations. Baert-Desurmont et al. (PMID:17228328) detected 7 MSH2 intragenic duplications in 11 families. The authors estimate that genomic duplications of MSH2 and MLH1 account for approximatly 1% of HNPCC cases. For additional information, see also PMID 16143124.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: Only intragenic duplications involving the duplication of an exon(s) have been described in families with HNPCC, which may cause disease through a loss of function mechanism. There have been no reports of complete MSH2 gene duplications associated with HNPCC or any other disease.