NDLI: Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies

Content Provider	Springer Nature Link
Author	Hardt, Karin Heick, Sven Boris Betz, Beate Goecke, Timm Yazdanparast, Haniyeh Küppers, Robin Servan, Kati Steinke, Verena Rahner, Nils Morak, Monika Holinski Feder, Elke Engel, Christoph Möslein, Gabriela Schackert, Hans Konrad Knebel Doeberitz, Magnus Pox, Christian Hegemann, Johannes H. Royer Pokora, Brigitte
Copyright Year	2011
Abstract	Missense mutations of the DNA mismatch repair gene MLH1 are found in a significant fraction of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer, HNPCC) and their pathogenicity often remains unclear. We report here all 88 MLH1 missense variants identified in families from the German HNPCC consortium with clinical details of these patients/families. We investigated 23 MLH1 missense variants by two functional in vivo assays in yeast; seven map to the ATPase and 16 to the protein interaction domain. In the yeast-2-hybrid (Y2H) assay three variants in the ATPase and twelve variants in the interaction domain showed no or a reduced interaction with PMS2; seven showed a normal and one a significantly higher interaction. Using the Lys2A 14 reporter system to study the dominant negative mutator effect (DNE), 16 variants showed no or a low mutator effect, suggesting that these are nonfunctional, three were intermediate and four wild type in this assay. The DNE and Y2H results were concordant for all variants in the interaction domain, whereas slightly divergent results were obtained for variants in the ATPase domain. Analysis of the stability of the missense proteins in yeast and human embryonic kidney cells (293T) revealed a very low expression for seven of the variants in yeast and for nine in human cells. In total 15 variants were classified as deleterious, five were classified as variants of unclassified significance (VUS) and three were basically normal in the functional assays, P603R, K618R, Q689R, suggesting that these are neutral.
Starting Page	273
Ending Page	284
Page Count	12
File Format	PDF
ISSN	13899600
Journal	Familial Cancer
Volume Number	10
Issue Number	2
e-ISSN	15737292
Language	English
Publisher	Springer Netherlands
Publisher Date	2011-03-15
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	HNPCC MLH1 Missense variants Variants of unclassified significance Cancer Research Biomedicine general Epidemiology Human Genetics
Content Type	Text
Resource Type	Article
Subject	Genetics Cancer Research Genetics (clinical) Oncology

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