Integrated analysis of unclassified variants in mismatch repair genes

Chiara Pastrello, Elisa Pin, Fabio Marroni, Chiara Bedin, Mara Fornasarig, Maria Grazia Tibiletti, Cristina Oliani, Maurizio Ponz De Leon, Emanuele Damiano Urso, Lara Della Puppa, Marco Agostini, Alessandra Viel

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Purpose: Lynch syndrome is a genetic disease that predisposes to colorectal tumors, caused by mutation in mismatch repair genes. The use of genetic tests to identify mutation carriers does not always give perfectly clear results, as happens when an unclassified variant is found. This study aimed to define the pathogenic role of 35 variants present in MSH2, MLH1, MSH6, and PMS2 genes identified in our 15-year case study. Methods: We collected clinical and molecular data of all carriers, and then we analyzed the variants pathogenic role with web tools and molecular analyses. Using a Bayesian approach, we derived a posterior probability of pathogenicity and classified each variant according to a standardized five-class system. Results: The MSH2 p.Pro349Arg, p.Met688Arg, the MLH1 p.Gly67Arg, p.Thr82Ala, p.Lys618Ala, the MSH6 p.Ala1236Pro, and the PMS2 p.Arg20Gln were classified as pathogenic, and the MSH2 p.Cys697Arg and the PMS2 p.Ser46Ile were classified as likely pathogenic. Seven variants were likely nonpathogenic, 3 were nonpathogenic, and 16 remained uncertain. CONCLUSION:: Quantitative assessment of several parameters and their integration in a multifactorial likelihood model is the method of choice for classifying the variants. As such classifications can be associated with surveillance and testing recommendations, the results and the method developed in our study can be useful for helping laboratory geneticists in evaluation of genetic tests and clinicians in the management of carriers.

Original languageEnglish (US)
Pages (from-to)115-124
Number of pages10
JournalGenetics in Medicine
Issue number2
StatePublished - Feb 2011


  • colorectal cancer
  • Lynch syndrome
  • mismatch repair
  • multifactorial likelihood
  • unclassified variant

ASJC Scopus subject areas

  • Genetics(clinical)


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