<unk>  is inherited in an autosomal dominant fashion.<unk>  is inherited in an autosomal dominant fashion. The hallmark of<unk>  is defective DNA mismatch repair, which causes an elevated rate of single nucleotide changes and microsatellite instability, also known as MSI-H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...). The 4 main genes involved in<unk>  normally encode for proteins that form dimers to function: # MLH1 protein dimerizes with PMS2 protein to form MutLα, which coordinates the binding of other proteins involved with mismatch repair like DNA helicase, single-stranded-DNA binding-protein (RPA), and DNA polymerases. # MSH2 protein dimerizes with MSH6 protein, which identifies mismatches via a sliding clamp model, a protein for scanning for errors. The impairment of either gene for the protein dimer impairs the protein function. These 4 genes are involved in error correction (mismatch repair), so dysfunction of the genes can lead to the inability to fix DNA replication errors and cause<unk> .<unk>  is known to be associated with other mutations in genes involved in the DNA mismatch repair pathway: OMIM name Genes implicated in<unk>  Frequency of mutations in<unk>  families Locus First publication<unk> 1 () MSH2/EPCAM approximately 60% 2p22 Fishel 1993<unk> 2 () MLH1 approximately 30% 3p21 Papadopoulos 1994<unk> 5 MSH6 7-10% 2p16 Miyaki 1997<unk> 4 PMS2 relatively infrequent 7p22 Nicolaides 1994<unk> 3 PMS1 case report 2q31-q33 Nicolaides 1994<unk> 6 TGFBR2 case report 3p22<unk> 7 MLH3 disputed 14q24.3 People with MSH6 mutations are more likely to be Amsterdam criteria II-negative. The presentation with MSH6 is slightly different from with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition. In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it. Up to 39% of families with mutations in an<unk>  gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in an<unk>  gene should be considered to have<unk>  regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many people who are at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article. Most people with<unk>  inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all people with an<unk>  gene mutation have a parent who had cancer. Some people develop<unk>  de-novo in a new generation, without inheriting the gene. These people are often only identified after developing an early-life colon cancer. Parents with<unk>  have a 50% chance of passing the genetic mutation on to each child. It is also important to note, that deleterious mutation in one of MMR genes alone is not sufficient to cause cancer, but that rather further mutations in other tumour suppressor genes need to occur.
Hereditary nonpolyposis colorectal cancer
Familial adenomatous polyposis
MUTYH-associated polyposis
Serrated polyposis syndrome
Hereditary diffuse gastric cancer
Juvenile polyposis syndrome
Attenuated familial adenomatous polyposis
Peutz–Jeghers syndrome