Familial Cancer

, Volume 12, Issue 2, pp 181–187

Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians


    • Department of Genetics, University Medical Center GroningenUniversity of Groningen
  • Marc S. Greenblatt
    • Department of Medicine and Vermont Cancer CenterUniversity of Vermont
  • Maurizio Genuardi
    • Department of Biomedical, Experimental and Clinical SciencesUniversity of Florence
    • Fiorgen Foundation for Pharmacogenomics
    • Tuscan Tumor Institute
Original Article

DOI: 10.1007/s10689-013-9629-8

Cite this article as:
Sijmons, R.H., Greenblatt, M.S. & Genuardi, M. Familial Cancer (2013) 12: 181. doi:10.1007/s10689-013-9629-8


Clinicians referring patients for genetic testing for Lynch syndrome will sooner or later receive results for DNA Mismatch Repair (MMR) genes reporting DNA changes that are unclear from a clinical point of view. These changes are referred to as variants of unknown, or unclear, clinical significance (VUS). In contrast to clearly pathogenic mutations, VUS do not firmly diagnose Lynch syndrome at the molecular level and cannot be used to identify with certainty any of the patients’ asymptomatic relatives as Lynch syndrome mutation carriers. The International database that collects MMR gene variants (www.insight-group.org/mutations) already lists more than 1,000 different VUSs and these variants are likely the tip of the iceberg. This paper aims at introducing non-geneticist clinicians to the topic of clinical MMR gene variant interpretation. Many lines of evidence are being used to classify VUS. Some are already familiar to clinicians and others may be less familiar but are expected to become important in clinical genetics in the coming years. Clinicians can play an important role in collecting the data needed to interpret the MMR variants detected in their patients.


Lynch syndromeHNPCCMismatch repair geneVariantsMissense mutationsPathogenicityClassification

Copyright information

© Springer Science+Business Media Dordrecht 2013