MSH2 c.1022T>C, p.Leu341Pro is a founder pathogenic variation and a major cause of Lynch syndrome in the North of France

Genes Chromosomes Cancer. 2020 Feb;59(2):111-118. doi: 10.1002/gcc.22804. Epub 2019 Sep 3.


Interpretation of missense variants remains a major challenge for genetic diagnosis, even in well-known genes such as the DNA-mismatch repair (MMR) genes involved in Lynch syndrome. We report the characterization of a variant in MSH2: c.1022T>C, which was identified in 20 apparently unrelated families living in the North of France. A total of 150 patients from 20 families were included in this study. Family segregation studies, tumor analyses and functional analyses at both the RNA and protein levels were performed. Founder effect was evaluated by haplotype analysis.We show that MSH2 c.1022T>C is a missense variant (p.Leu341Pro) that affects protein stability. This variant is frequent in the North of France (7.7% of pathogenic variations identified in MMR genes), and is located on an ancestral haplotype. It is associated with a high risk of a broad tumor spectrum including brain and cutaneous cancers. The MSH2 c.1022T>C variant is a pathogenic founder variation associated with a high risk of cancer. These findings have important implications for genetic counseling and management of variant carriers.

Keywords: MSH2; Lynch syndrome; founder pathogenic variant; hereditary cancer; missense variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Mismatch Repair
  • Exons
  • Female
  • Founder Effect
  • France / epidemiology
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Haplotypes
  • Humans
  • Male
  • Microsatellite Instability
  • Middle Aged
  • MutS Homolog 2 Protein / genetics*
  • MutS Homolog 2 Protein / metabolism
  • Mutation, Missense
  • Pedigree
  • Polymorphism, Single Nucleotide


  • MSH2 protein, human
  • MutS Homolog 2 Protein