caa a22 4500 445331445 CHVBK 20180317142738.0 cr unu---uuuuu 170323e20110601xx s 000 0 eng 10.1007/s10689-010-9409-7 doi (NATIONALLICENCE)springer-10.1007/s10689-010-9409-7 Non-truncating hMLH1 variants identified in Slovenian gastric cancer patients are not associated with Lynch Syndrome: a functional analysis report [Elektronische Daten] [Matjaz Vogelsang, Radovan Komel] Hereditary non-polyposis colorectal cancer is the most common known genetic syndrome that predisposes to various types of cancer including gastric cancer and occures mainly due to pathogenic germline mutations in DNA mismatch repair (MMR) genes, such as MLH1, MSH2 and MSH6. Impaired MMR activity can lead to microsatellite instability (MSI) in tumor tissues. Interpreting the pathogenic significance of identified mutations in MMR genes, especially missense alterations and short in-frame deletions and insertions is challenging and functional analysis is often needed to accurately assess their pathogenicities. The purpose of this study was to evaluate functional significance of MLH1 missense mutations, previously identified in unrelated Slovenian patients with MSI-positive gastric carinomas. A novel in vivo yeast-based approach and in silico predictions were used. Variant E433Q was characterized for the first time and was shown to have no effect on MLH1 protein function. Functional analysis of amino acid rearrangement K618A, with previously reported contradictory results of its pathogenicity, suggests that the variant is a neutral polymorphism. Results of our study imply that there is either germline mutation or an epigenetic inactivation of another MMR gene, which causes MSI phenotype in the referred gastric cancer cases. Springer Science+Business Media B.V., 2010 HNPCC nationallicence Gastric cancer nationallicence MSI nationallicence hMLH1 variants nationallicence Functional analysis nationallicence Yeast nationallicence CORE : counterselectable reporter nationallicence CRC : colorectal cancer nationallicence GC : gastric cancer nationallicence HNPCC : Hereditary non-polyposis colorectal cancer nationallicence IHC : immunohistochemistry nationallicence MMR DNA : mismatch repair nationallicence MSI : microsatellite instability nationallicence PolyPhen : polymorphism phenotype nationallicence SIFT : sorting intolerant from tolerant nationallicence UV : unclassified variant nationallicence Vogelsang Matjaz Department for Biosynthesis and Biotransformation, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia aut Komel Radovan Department for Biosynthesis and Biotransformation, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia aut Familial Cancer Springer Netherlands 10/2(2011-06-01), 255-263 1389-9600 10:2<255 2011 10 10689 https://doi.org/10.1007/s10689-010-9409-7 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10689-010-9409-7 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Vogelsang Matjaz Department for Biosynthesis and Biotransformation, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia aut NATIONALLICENCE 700 1- Komel Radovan Department for Biosynthesis and Biotransformation, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia aut NATIONALLICENCE 773 0- Familial Cancer Springer Netherlands 10/2(2011-06-01), 255-263 1389-9600 10:2<255 2011 10 10689 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer