caa a22 4500 445330996 CHVBK 20180317142737.0 cr unu---uuuuu 170323e20110901xx s 000 0 eng 10.1007/s10689-011-9436-z doi (NATIONALLICENCE)springer-10.1007/s10689-011-9436-z A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance—functional analysis reveals the pathogenic one [Elektronische Daten] [Jukka Kantelinen, Thomas Hansen, Minttu Kansikas, Lotte Krogh, Mari Korhonen, Saara Ollila, Minna Nyström, Anne-Marie Gerdes, Reetta Kariola] Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS family carrying VUS in both MSH2 (c.2768T>A, p.Val923Glu) and MSH6 (c.3563G>A, p.Ser1188Asn). Two colorectal cancer (CRC) patients were studied for mutations and identified as carriers of both variants. In spite of a relatively high mean age of cancer onset (59.5years) in the family, many CRC patients and the tumor pathological data suggested that the missense variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence that instead of MSH2 p.Val923Glu the MSH6 p.Ser1188Asn variant is completely MMR-deficient, the present study confirms the previous findings, and suggests that MSH6 (c.3563G>A, p.Ser1188Asn) is the pathogenic mutation in the family. Moreover, our results strongly support the strategy to functionally assess all identified VUS before predictive gene testing and genetic counseling are offered to a family. Springer Science+Business Media B.V., 2011 Functional analysis nationallicence Lynch syndrome nationallicence MSH2 nationallicence MSH6 nationallicence Variants of uncertain significance (VUS) nationallicence AC : Amsterdam criteria nationallicence CRC : Colorectal cancer nationallicence EPCAM : Epithelial cell adhesion molecule nationallicence HNPCC : Hereditary non-polyposis colorectal cancer nationallicence IHC : Immunohistochemical nationallicence LS : Lynch syndrome nationallicence MMR : Mismatch repair nationallicence MSI : Microsatellite instability nationallicence NE : Nuclear extract nationallicence TE : Total extract nationallicence VUS : Variants of uncertain significance nationallicence WT : Wild type nationallicence Kantelinen Jukka Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut Hansen Thomas Department of Clinical Biochemistry, Section of Genomic Medicine, Rigshospitalet and Copenhagen University, Copenhagen, Denmark aut Kansikas Minttu Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut Krogh Lotte Department of Clinical Genetics, Odense University Hospital, Odense, Denmark aut Korhonen Mari Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut Ollila Saara Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut Nyström Minna Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut Gerdes Anne-Marie Department of Clinical Genetics, Rigshospital and Copenhagen University, Copenhagen, Denmark aut Kariola Reetta Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut Familial Cancer Springer Netherlands 10/3(2011-09-01), 515-520 1389-9600 10:3<515 2011 10 10689 https://doi.org/10.1007/s10689-011-9436-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10689-011-9436-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kantelinen Jukka Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut NATIONALLICENCE 700 1- Hansen Thomas Department of Clinical Biochemistry, Section of Genomic Medicine, Rigshospitalet and Copenhagen University, Copenhagen, Denmark aut NATIONALLICENCE 700 1- Kansikas Minttu Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut NATIONALLICENCE 700 1- Krogh Lotte Department of Clinical Genetics, Odense University Hospital, Odense, Denmark aut NATIONALLICENCE 700 1- Korhonen Mari Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut NATIONALLICENCE 700 1- Ollila Saara Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut NATIONALLICENCE 700 1- Nyström Minna Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut NATIONALLICENCE 700 1- Gerdes Anne-Marie Department of Clinical Genetics, Rigshospital and Copenhagen University, Copenhagen, Denmark aut NATIONALLICENCE 700 1- Kariola Reetta Department of Biosciences, Genetics, University of Helsinki, P.O. Box 56 (Viikinkaari 5), 00014, Helsinki, Finland aut NATIONALLICENCE 773 0- Familial Cancer Springer Netherlands 10/3(2011-09-01), 515-520 1389-9600 10:3<515 2011 10 10689 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer