Lynch syndrome [MONDO:0005835], also known as Hereditary Nonpolyposis Colon Cancer [MONDO:0018630], is a group of autosomal dominant cancer predisposing syndrome. It is characterized by a familial predisposition to early-onset colorectal carcinoma (CRC) and extra- colonic tumors of the gastrointestinal, urological and female reproductive tracts. MSH2 has been linked to Lynch Syndrome, or HNPCC in the early 1990s (PMID: 8261515 and 8252616). Of note, this gene has also been implicated in autosomal recessive mismatch repair cancer syndrome 1 (MONDO:0010159), which has been assessed separately. MSH2 gene encodes MSH2 protein, which heterodimerizes with MSH6 or MSH3 to form MSH2-MSH6 or MSH2-MSH3 complex (also named MutSα and MutSβ, respectively). Both MutSα and MutSβ are required for the DNA mismatch repair (MMR) pathway. Defective MMR pathway is responsible for microsatellite instability, a type of genomic instability that is characteristic for tumor cells. Loss of function variants in MSH2 gene have been repetitively reported in families and individuals from various populations. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Eight loss of function variants in this gene reported in 9 probands from 9 families in 2 publications (PMID:18566915, 32161499) is included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by expression, functional studies (6 points) demonstrating MSH2’s role in mismatch repair and mouse models (PMIDs: 19324997, 7550317, 7628020). Homozygous Msh2-/- mice began, with high frequency, to develop lymphoid tumors containing microsatellite instabilities at an early age. In addition, Msh2-deficient mouse ES cells lost mismatch binding and acquired microsatellite instability. In summary, MSH2 is definitively associated with autosomal dominant Lynch syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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