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Genetics and Genomics

Lynch syndrome, molecular mechanisms and variant classification

Abstract

Patients with the heritable cancer disease, Lynch syndrome, carry germline variants in the MLH1, MSH2, MSH6 and PMS2 genes, encoding the central components of the DNA mismatch repair system. Loss-of-function variants disrupt the DNA mismatch repair system and give rise to a detrimental increase in the cellular mutational burden and cancer development. The treatment prospects for Lynch syndrome rely heavily on early diagnosis; however, accurate diagnosis is inextricably linked to correct clinical interpretation of individual variants. Protein variant classification traditionally relies on cumulative information from occurrence in patients, as well as experimental testing of the individual variants. The complexity of variant classification is due to (1) that variants of unknown significance are rare in the population and phenotypic information on the specific variants is missing, and (2) that individual variant testing is challenging, costly and slow. Here, we summarise recent developments in high-throughput technologies and computational prediction tools for the assessment of variants of unknown significance in Lynch syndrome. These approaches may vastly increase the number of interpretable variants and could also provide important mechanistic insights into the disease. These insights may in turn pave the road towards developing personalised treatment approaches for Lynch syndrome.

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Fig. 1: The human DNA mismatch repair (MMR) system.
Fig. 2: Proteasomal degradation of misfolded proteins.
Fig. 3: Overview of tools used for testing individual variant effects.

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Funding

Our research in this area is funded by the Novo Nordisk Foundation Challenge programme PRISM (NNFOC180033950; to AS, KLL and RHP), the Lundbeck Foundation (R272-2017-4528 to AS), and the Danish Council for Independent Research, Natural Sciences (7014-00039B to RHP).

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ABA and SVN prepared the figures. ABA, SVN, IB, AS, KLL and RHP wrote the manuscript.

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Correspondence to Sofie V. Nielsen, Kresten Lindorff-Larsen or Rasmus Hartmann-Petersen.

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Abildgaard, A.B., Nielsen, S.V., Bernstein, I. et al. Lynch syndrome, molecular mechanisms and variant classification. Br J Cancer (2022). https://doi.org/10.1038/s41416-022-02059-z

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