MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer

Milena Di Leo1, Alessandro Mannucci2, Raffaella Alessia Zuppardo2, Federica Calabrese2, Stefano Crippa3, Paola Carrera4, Mariagrazia Patricelli4, Annalisa Russo Raucci4, Dejan Lazarevic5, Francesca Giannese5, Giovanni Tonon5, Maurizio Ferrari4, Pier Alberto Testoni2, Giulia Martina Cavestro2

1Humanitas Clinical and Research Center – IRCCS, Digestive Endoscopy Unit, Division of Gastroenterology, Milan, Italy. 2Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, Vita-Salute San Raffaele University, IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy. 3San Raffaele Hospital, Pancreatic Surgery, Pancreas Translational and Clinical Research Center, Milan, Italy. 4Unit of Genomics for Human Disease Diagnosis, Division of Genetics and Cell Biology and Laboratory of Clinical Molecular Biology and Cytogenetics, IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy. 5Center for Translational Genomics and Bio Informatics- IRCCS Ospedale San Raffaele Scientific Institute, Milan, Italy



Lynch syndrome (LS) is characterised by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. LS is characterised by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent LS and pancreatic familial carcinoma in the absence of colorectal neoplasia.


A family with familial pancreatic cancer and other tumours (gastric, endometrial) was studied. Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes.


We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma.

Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75 years old, 45 years old and 17 years old) developed any cancer yet.


LS should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.