ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: LYNCH SYNDROME I
Evidence for haploinsufficiency phenotype
PubMed ID Description
10850409 Germline mutations 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 mutations were detected in the MSH2 gene (4 frameshift, 4 nonsense, 1 splice site, 2 missese). One of the genomic rearrangments is a previously reported paracentric inversion of chromosome 2 (PMID 12203789) the remainder were exonic deletions of various lengths. The author also descibed a family that was negative for mutations within the MSH2 gene and other mis match repair (MMR) genes that had classical HNPCC and showed a high microsattelite insatbility phenotype and loss of MSH2 protein expression by IHC indicating the functional impairment of MSH2. Additional articles showing intragenic deletions include PMID 15949572, 9843200
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.
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 mutations including genomic deletions (including complete gene deletions) and rearrangemnts and that mutation analysis of the MSH2 gene should include the examination of its genomic structure by Southern blot.

Haploinsufficiency phenotype 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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

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.