Identification of Lynch syndrome risk variants in the Romanian population

J Cell Mol Med. 2018 Dec;22(12):6068-6076. doi: 10.1111/jcmm.13881. Epub 2018 Oct 16.


Two familial forms of colorectal cancer (CRC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP), are caused by rare mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the genes APC and MUTYH, respectively. No information is available on the presence of high-risk CRC mutations in the Romanian population. We performed whole-genome sequencing of 61 Romanian CRC cases with a family history of cancer and/or early onset of disease, focusing the analysis on candidate variants in the LS and FAP genes. The frequencies of all candidate variants were assessed in a cohort of 688 CRC cases and 4567 controls. Immunohistochemical (IHC) staining for MLH1, MSH2, MSH6, and PMS2 was performed on tumour tissue. We identified 11 candidate variants in 11 cases; six variants in MLH1, one in MSH6, one in PMS2, and three in APC. Combining information on the predicted impact of the variants on the proteins, IHC results and previous reports, we found three novel pathogenic variants (MLH1:p.Lys84ThrfsTer4, MLH1:p.Ala586CysfsTer7, PMS2:p.Arg211ThrfsTer38), and two novel variants that are unlikely to be pathogenic. Also, we confirmed three previously published pathogenic LS variants and suggest to reclassify a previously reported variant of uncertain significance to pathogenic (MLH1:c.1559-1G>C).

Keywords: Colorectal cancer; Lynch syndrome; MLH1, MSH2, MSH6, MUTYH, PMS2; Romania.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / epidemiology
  • Adenomatous Polyposis Coli / genetics*
  • Adenomatous Polyposis Coli / pathology
  • Adult
  • Aged
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Glycosylases / genetics
  • DNA Methylation / genetics
  • DNA Mismatch Repair / genetics*
  • DNA-Binding Proteins / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Male
  • Middle Aged
  • Mismatch Repair Endonuclease PMS2 / genetics
  • MutL Protein Homolog 1 / genetics
  • MutS Homolog 2 Protein / genetics
  • Mutation
  • Risk Factors
  • Romania / epidemiology


  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • DNA Glycosylases
  • mutY adenine glycosylase
  • PMS2 protein, human
  • MSH2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein