A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants

Mark Drost, Jose B. M. Zonneveld, Sandrine van Hees, Lene Juel Rasmussen, Robert M. W. Hofstra, Niels de Wind*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    32 Citations (Scopus)

    Abstract

    Lynch syndrome (LS) is an autosomal dominant disorder that predisposes to colon, endometrial, and other cancers. LS is caused by a heterozygous germline mutation in one of the DNA mismatch repair (MMR) genes. A significant proportion of all mutations found in suspected LS patients comprises single amino acid alterations. The pathogenicity of these variants of uncertain significance (VUS) is difficult to assess, precluding diagnosis of carriers and their relatives. Here we present a rapid cell-free assay to investigate MMR activity of MSH2 or MSH6 VUS. We used this assay to analyze a series of MSH2 and MSH6 VUS, selected from the Leiden Open Variation Database. Whereas a significant fraction of the MSH2 VUS has lost MMR activity, suggesting pathogenicity, the large majority of the MSH6 VUS appears MMR proficient. We anticipate that this assay will be an important tool in the development of a comprehensive and widely applicable diagnostic procedure for LS-associated VUS. Hum Mutat 33:488494, 2012. (C) 2011 Wiley Periodicals, Inc.

    Original languageEnglish
    Pages (from-to)488-494
    Number of pages7
    JournalHuman Mutation
    Volume33
    Issue number3
    DOIs
    Publication statusPublished - Mar-2012

    Keywords

    • Lynch syndrome
    • DNA mismatch repair
    • variants of uncertain significance
    • functional assay
    • MSH2
    • MSH6
    • NONPOLYPOSIS COLORECTAL-CANCER
    • MISMATCH REPAIR GENES
    • FUNCTIONAL-ANALYSIS
    • DNA-REPAIR
    • MICROSATELLITE INSTABILITY
    • UNCLASSIFIED VARIANTS
    • NUCLEAR EXTRACTS
    • MUTATIONS
    • CLASSIFICATION
    • PROTEIN

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