Lynch Syndrome via the MSH2 Gene

Lynch Syndrome, also called Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is an inherited cancer syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes. MMR genes encode proteins that repair small sequence errors, or mismatches, during DNA replication. Pathogenic variants in a single mismatch repair gene can cause widespread genomic instability characterized by the expansion or contraction of short tandem repeat sequences, or microsatellites (Grady and Carethers. 2008. PubMed ID: 18773902). This phenomenon of microsatellite instability (MSI) leads to somatic mutations in oncogenes and/or tumor suppressor genes, including TGFβIIR and NF1 among others (Wang et al. 2003. PubMed ID: 12522551). As a result, Lynch Syndrome is marked by early onset and high lifetime risk of cancer, particularly in the right colon but also in the endometrium, ovary, stomach, bile duct, kidney, bladder, ureter, and brain (Jang and Chung. 2010. PubMed ID: 20559516). Clinical hallmarks of Lynch Syndrome, as delineated by the Amsterdam criteria, include heritable colorectal (Type I) or extracolonic (Type II) cancer, present in at least three relatives over at least two consecutive generations, with an onset of cancer before the age of 50 in at least one case, and pathological MSI within tumors (Vasen et al. 1999. PubMed ID: 10348829).

Lynch Syndrome is an autosomal dominant disease and caused by germline pathogenic variants in one of six MMR genes: MLH1, MSH2, MSH6 and PMS2 (Peltomäki and Vasen. 2004. PubMed ID: 15528792). Pathogenic variants in MLH1 and MSH2 account for 80-90% of all Lynch patients and most frequently occur in families meeting the Amsterdam I criteria. Pathogenic variants in MSH6 and PMS2 account for the remaining Lynch patients, and are often found in families with atypical HPNCC symptoms, such as low rates of MSI and/or extracolonic carcinomas.

More than 500 pathogenic variants have been reported in the MSH2 gene, half of which are single nucleotide substitutions, small insertions/deletions or splice site mutations (Human Gene Mutation Database, www.hgmd.cf.ac.uk; www.insight-group.org). The other half are large deletions and not detectable by sequencing. In particular, a deletion of exons 1-6 is found in many North American families, but not found in European or Australian patients (Lynch et al. 2004. PubMed ID: 14871915). A germline inversion of exons 1-7 in MSH2 has been reported in fourteen individuals from eleven un-related families clinically presenting with Lynch syndrome associated phenotypes including colorectal, endometrial, gastric, and ovarian cancer (Wagner et al. 2002. PubMed ID: 12203789; Rhees et al. 2013. PubMed ID: 24114314; Mork et al. 2016. PubMed ID: 28004223).

Depending on the clinical criteria used to make a diagnosis (Amsterdam or “Revised Bethesda”), 15-20% of Lynch patients have a detectable MSH2 pathogenic variant (Syngal et al. 2000. PubMed ID: 10978352).

This test provides full coverage of all coding exons of the MSH2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing. It also includes testing for the inversion of exons 1-7 in MSH2.