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


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.

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

Figure 1.

The mammalian DNA mismatch repair pathway. The replicative DNA polymerase misincorporates a nucleotide (X) during DNA replication. The MSH2‐MSH6 heterodimer recognises and binds to the mismatch, followed by mismatch validation by ADP→ATP exchange. This complex recruits the MLH1‐PMS2 heterodimer and the latent endonuclease activity of PMS2 introduces a nick in the daughter strand, 5′ of the misincorporation. The nick serves as entry point for the EXO1 exonuclease that degrades a patch of the daughter strand that includes the misincorporation. The remaining single‐stranded DNA gap is covered by the single‐strand DNA binding protein RPA and filled by the replicative DNA polymerase.

Figure 2.

Proposed steps for the diagnostic assessment of mismatch repair protein VUS. The figure shows the proposed test as well as the conclusions that can be drawn based on the results of the assays.



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Further Reading

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Sijmons RH, Greenblatt MS and Genuardi M (2013) Gene variants of unknown clinical significance in Lynch syndrome. An introduction for clinicians. Familial Cancer 12: 181–187.

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Rasmussen, Lene Juel, and Heinen, Christopher D(Apr 2014) Assessing Genetic Variants of Uncertain Significance: The Example of Lynch Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025219]