Case study A rare MSH2 mutation causes defective binding to hMSH6, normal hMSH2 staining, and loss of hMSH6 at advanced cancer stage ☆,☆☆ Daria Carmela Loconte PhD a,1 , Margherita Patruno MD a,1 , Patrizia Lastella MD, PhD b,1 , Carmela Di Gregorio MD c , Valentina Grossi PhD d , Giovanna Forte BScT e , Giuseppe Ingravallo MD f , Dora Varvara MD a , Rosanna Bagnulo BScT a , Cristiano Simone MD, PhD a,d , Nicoletta Resta PhD a , Alessandro Stella PhD a, ⁎ a Division of Medical Genetics, Department of Biomedical Sciences and Human Oncology, Università di Bari “Aldo Moro”, 70124 Bari, Italy b Geriatric Unit and Rare Disease Center, University Hospital of Bari, 70124 Bari, Italy c Department of Laboratory, Pathology, and Legal Medicine, University Hospital Polyclinic of Modena, 41124 Modena, Italy d National Cancer Institute, IRCCS Oncologico Giovanni Paolo II, 70124 Bari, Italy e Cancer Genetics Laboratory, IRCCS "De Bellis", 70013 Castellana Grotte BA, Italy f Department of Emergency and Organ Transplant, Universita' di Bari "Aldo Moro", 70124 Bari, Italy Received 20 November 2013; revised 22 May 2014; accepted 28 May 2014 Keywords: Lynch syndrome; Mismatch repair; MSH2; MSH6; Second hit; Variants of unknown significance Summary Lynch syndrome is caused by germline mutations in 1 of the 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2). Mutations in MSH2 cause concomitant loss of hMSH6, whereas MLH1 mutations lead to concurrent loss of PMS2. Much less frequent mutations in MSH6 or PMS2 are associated with the isolated loss of the corresponding proteins. We here demonstrate the causative role of the first germline mutation of MSH2, c.1249-1251 dupGTT (p.417 V-418I dupV), associated with normal hMSH2 expression and lack of hMSH6 protein despite a normal MSH6 gene sequence. hMSH6 protein was completely lost only in advanced cancer stages due to 2 different “second hits”: a whole MSH2 gene deletion and a frame-shifting insertion in the MSH6 (C) 8 repeat in the coding sequence. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Germline mutations in mismatch repair (MMR) genes cause Lynch syndrome (LS) or hereditary nonpolyposis colorectal cancer (CRC), an autosomal dominant disorder that predisposes to high risk of developing cancer. Three percent to 6% of all CRCs are estimated to be due to the presence of MMR gene mutations [1]. MLH1 and MSH2 are the most prevalent mutated MMR genes, with mutations in MSH6 and PMS2 being less frequently www.elsevier.com/locate/humpath ☆ Competing interests: The authors declare that they have no competing interests. ☆☆ Funding/Support: This work was partially supported by grants Ricerca Scientifica di Ateneo Università degli Studi di Bari “Aldo Moro” (Bari, Italy), contract number H95E10000710005 to A.S., Investigator Grant 2010 (IG10177) from the Italian Association for Cancer Research to (Milano, Italy), and Futuro in Ricerca grant RBFR 12VP3Q_003 from MIUR to C.S.V.G. is supported by a fellowship from the ITALIAN ASSOCIATION FOR CANCER RESEARCH (AIRC, Milano, Italy) to C.S. ⁎ Corresponding author at: UOC Laboratorio di Genetica Medica, Azienda Ospedaliero–Universitaria Policlinico di Bari, Piazzale Giulio Cesare 11, 70124 Bari, Italy. E-mail address: alessandro.stella@uniba.it (A. Stella). 1 These authors contributed equally to this work. http://dx.doi.org/10.1016/j.humpath.2014.05.019 0046-8177/© 2014 Elsevier Inc. All rights reserved. Human Pathology (2014) 45, 2162–2167