An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC Yael Goldberg • Rinnat M. Porat • Inbal Kedar • Chen Shochat • Daliah Galinsky • Tamar Hamburger • Ayala Hubert • Hana Strul • Revital Kariiv • Liat Ben-Avi • Moran Savion • Eli Pikarsky • Dvorah Abeliovich • Dani Bercovich • Israela Lerer • Tamar Peretz Published online: 23 October 2009 Ó Springer Science+Business Media B.V. 2009 Abstract Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work- up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ash- kenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G [ C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_ 3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G [ C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome. Keywords HNPCC Á BRCA Á MSH6 Á Founder Á Ashkenazi Á MMR Abbreviations AC Amsterdam criteria BC Breast cancer CRC Colorectal cancer DHPLC Denaturing high performance liquid chromatography HBOC Hereditary breast ovarian cancer HNPCC Hereditary non-polyposis colorectal cancer IHC Immunohistochemistry MMR Mismatch repair MSI Microsatellite instability Y. Goldberg (&) Á D. Galinsky Á T. Hamburger Á A. Hubert Á T. Peretz Sharret Institute of Oncology, Hadassah-Hebrew University Medical Center, Kyriat Hadassah, POB 12000, 91120 Jerusalem, Israel e-mail: yaelg@hadassah.org.il R. M. Porat Á E. Pikarsky Department of Pathology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel H. Strul Á R. Kariiv Department of Gastroenterology, TASMC, Tel Aviv, Israel I. Kedar The Raphael Recanati Genetics Institute, The Rabin Medical Center, Petah Tikva, Israel C. Shochat Á D. Bercovich The Human Molecular Genetics & Pharmacogenetics Lab, Migal—Galilee Bio-Technology Center, Kiryat Shmona, Israel L. Ben-Avi Á M. Savion Á D. Abeliovich Á I. Lerer Department of Human Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel D. Bercovich Tel Hai Academic College, Israewl, Israel 123 Familial Cancer (2010) 9:141–150 DOI 10.1007/s10689-009-9298-9