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Assessing Genetic Variants of Uncertain Significance: The Example of Lynch Syndrome

  1. Lene Juel Rasmussen1,
  2. Christopher D Heinen2

Published Online: 15 APR 2014

DOI: 10.1002/9780470015902.a0025219



How to Cite

Rasmussen, L. J. and Heinen, C. D. 2014. Assessing Genetic Variants of Uncertain Significance: The Example of Lynch Syndrome. eLS. .

Author Information

  1. 1

    University of Copenhagen, Copenhagen, Denmark

  2. 2

    University of Connecticut Health Center, Farmington, Connecticut, USA

Publication History

  1. Published Online: 15 APR 2014


A significant fraction of cancer is the result of genetic predisposition. Frequently, in patients with suspected cancer predisposition, subtle variations are found in predisposing genes. Currently, it is often not possible to determine whether such variants are pathogenic, thus they are termed variants of uncertain significance (VUS). This leads to anxiety in carriers and noncarrying relatives alike, as well as to an unnecessary burden to preventive healthcare. The establishment of procedures that enable the diagnostic assessment of VUSs in individuals are discussed and hereditary colorectal cancer syndrome, Lynch syndrome, is used as an example. This challenge is addressed by illustrating the importance of combining genetic and functional data in future strategies to assess VUS. The proposed strategies combine clinical genetic, analytical, functional and in silico approaches.

Key Concepts:

  • Biological knowledge is essential for functional characterisation of variants of uncertain significance (VUS).

  • Diagnosis of inherited cancer disorders requires integration of clinical and biological data.

  • DNA mismatch repair is defective in Lynch syndrome.

  • Deficient DNA mismatch repair causes genomic instability including microsatellite instability.

  • Classification of variants of uncertain significance is important for implementation of cancer prevention strategies.


  • variants of uncertain significance;
  • Lynch syndrome;
  • mismatch repair genes;
  • missense mutations;
  • functional assays