Lynch Syndrome/Constitutional Mismatch Repair Deficiency Panel

Lynch syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), is an inherited cancer syndrome mainly 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 mismatch repair genes can cause widespread genomic instability characterized by the expansion and contraction of short tandem repeat sequences (microsatellites) (Grady and Carethers. 2008. PubMed ID: 18773902). As a result, Lynch syndrome is marked by early onset and a 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 exclusion of familial adenomatous polyposis (FAP) (Vasen et al. 1999. PubMed ID: 10348829).

Lynch syndrome is an autosomal dominant disease caused by germline variants in one of five described MMR genes: MLH1, MSH2, MSH6, PMS2 and EPCAM (Idos and Valle. 2021. PubMed ID: 20301390).

Pathogenic variants in another gene, EPCAM, which encodes a calcium-independent cell adhesion molecule and not a mismatch repair protein, are also involved in Lynch syndrome. Germline pathogenic variants in the EPCAM gene can cause inactivation of the nearby MSH2 gene via hypermethylation in 1-3% of individuals with Lynch syndrome (Kohlmann and Gruber. 2014. PubMed ID: 20301390). The only reported pathogenic variants in the EPCAM gene that are causative for Lynch Syndrome are large deletions (Human Gene Mutation Database; www.insight-group.org). The cumulative incidence of colon cancer risk from EPCAM deletions has been estimated to be 75% by 70 years of age, and for endometrial cancer in women to be 12% (Kempers et al. 2011. PubMed ID: 21145788).

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).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Lynch syndrome is attributed to pathogenic sequence variants in the MLH1, MSH2, MSH6, and PMS2 genes in approximately 50%, 40%, 7-10% and <5% of cases, respectively (Kohlmann and Gruber. 2014. PubMed ID: 20301390). The majority of these variants are single nucleotide substitutions or small insertions and deletions. Missense, nonsense and splicing EPCAM pathogenic variants are involved in congenital tufting enteropathy (Human Gene Mutation Database), while EPCAM deletions account for 1-3% of Lynch syndrome cases (Kohlmann and Gruber. 2014. PubMed ID: 20301390). Large deletions and genetic rearrangements account for 20%, 5%, 20%, 7%, and 100% of identifiable pathogenic variants in the MSH2, MLH1, PMS2, MSH6, and EPCAM genes (Kohlmann and Gruber. 2014. PubMed ID: 20301390).

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

This test also includes analysis of the inversion of exons 1-7 in MSH2.

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is included in this test.