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GENATLAS PHENOTYPE
last update : 27-04-2011
Symbol HNPCC1
Location 2p21
Name hereditary nonpolyposis colorectal cancer, type 1
Other name(s)
  • Lynch syndrome I
  • colon cancer, familial nonpolyposis, type 1
    • Corresponding gene MSH2 , EPCAM
    Other symbol(s) COCA1, CRC1, HNPCC, FCC1
    Main clinical features
  • colorectal carcinoma in at least 3 relatives belonging to 2 or more successive generations, with the age of onset less than 50 years in at least 1 patient;
  • in addition to the colon (most often the right side), organs commonly affected with cancer include the endometrium, stomach, biliary and pancreatic system, and urinary tract
  • microsatellite instability
    • Genetic determination autosomal dominant
    Related entries HNPCC1-6
    Function/system disorder digestive tract/gastrointestinal
    neoplasia
    Type susceptibility factor
    Gene product
    Name PMS1 protein homolog 2, dimerize with the product of MLH1
    Mechanism(s)
    Gene mutationChromosome rearrangementEffectComments
    deletion     large genomic deletions in both MSH2 and MLH1 genes may play a considerable role in the pathogenesis of HNPCC
    various types     over 170 mutations identified
    duplication     genomic duplications
    deletion     American Founder Mutation (AFM)= exons 1-6 deletion
    Remark(s)
  • susceptibility to HNPCC/Lynch syndrome have been convincely linked to mutations in four MMR genes: MSH2 (~50 percent), MLH1(~40 percent), MSH6(~10 percent), and PMS2. Clinical significance of mutations in MLH3 and PMS1 are less clear ;
  • large germline deletions encompassing the last exons of the TACSTD1[EPCAM] gene, upstream of MSH2 implicated in HNPCC1 (Kovacs 2009) yields heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome.
  • pathogenic missense mutations in MSH2 may interfere with different mechanisms that tend to cluster in separate protein domains with varying effects on protein stability (Ollila 2008)
    • Genotype/Phenotype correlations the inheritance of two MMR gene mutations is a separate entity from Lynch I or II or the subtypes Turcot and Muir-Torre.