Cornelia Meisel1,2,3, Carolin Eva Sadowski1,2,3, Daniela Kohlstedt1,2,3, Katja Keller1,2,3, Franziska Stäritz1,2,3, Nannette Grübling1,2,3, Kerstin Becker4,5, Luisa Mackenroth2,3,4, Andreas Rump2,3,4, Evelin Schröck2,3,4, Norbert Arnold6, Pauline Wimberger1,2,3, Karin Kast7,8,9. 1. Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany. 2. National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany. 3. German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. 4. Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany. 5. Medical Genetic Center, Munich, Germany. 6. Department of Obstetrics and Gynecology, University Hospital of Schleswig-Holstein, University Kiel, Kiel, Germany. 7. Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany. karin.kast@uniklinikum-dresden.de. 8. National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany. karin.kast@uniklinikum-dresden.de. 9. German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. karin.kast@uniklinikum-dresden.de.
Abstract
BACKGROUND: Determination of mutation status of BRCA1 and BRCA2 has become part of the clinical routine. However, the spectrum of genetic variants differs between populations. The aim of this study was to deliver a comprehensive description of all detected variants. METHODS: In families fulfilling one of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) criteria for genetic testing, one affected was chosen for analysis. DNA of blood lymphocytes was amplified by PCR and prescreened by DHPLC. Aberrant fragments were sequenced. All coding exons and splice sites of BRCA1 and BRCA2 were analyzed. Screening for large rearrangements in both genes was performed by MLPA. RESULTS: Of 523 index patients, 121 (23.1%) were found to carry a pathogenic or likely pathogenic (class 4/5) mutation. A variant of unknown significance (VUS) was detected in 73/523 patients (13.9%). Two mutations p.Gln1756Profs*74 and p.Cys61Gly comprised 42.3% (n = 33/78) of all detected pathogenic mutations in BRCA1. Most of the other mutations were unique mutations. The most frequently detected mutation in BRCA2 was p.Val1283Lys (13.9%; n = 6/43). Altogether, 101 different neutral genetic variants were counted in BRCA1 (n = 35) and in BRCA2 (n = 66). CONCLUSION: The two most frequently detected mutations are founder mutations in Poland and Czech Republic. More similarities seem to be shared with our direct neighbor countries compared to other European countries. For comparison of the extended genotype, a shared database is needed.
BACKGROUND: Determination of mutation status of BRCA1 and BRCA2 has become part of the clinical routine. However, the spectrum of genetic variants differs between populations. The aim of this study was to deliver a comprehensive description of all detected variants. METHODS: In families fulfilling one of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) criteria for genetic testing, one affected was chosen for analysis. DNA of blood lymphocytes was amplified by PCR and prescreened by DHPLC. Aberrant fragments were sequenced. All coding exons and splice sites of BRCA1 and BRCA2 were analyzed. Screening for large rearrangements in both genes was performed by MLPA. RESULTS: Of 523 index patients, 121 (23.1%) were found to carry a pathogenic or likely pathogenic (class 4/5) mutation. A variant of unknown significance (VUS) was detected in 73/523 patients (13.9%). Two mutations p.Gln1756Profs*74 and p.Cys61Gly comprised 42.3% (n = 33/78) of all detected pathogenic mutations in BRCA1. Most of the other mutations were unique mutations. The most frequently detected mutation in BRCA2 was p.Val1283Lys (13.9%; n = 6/43). Altogether, 101 different neutral genetic variants were counted in BRCA1 (n = 35) and in BRCA2 (n = 66). CONCLUSION: The two most frequently detected mutations are founder mutations in Poland and Czech Republic. More similarities seem to be shared with our direct neighbor countries compared to other European countries. For comparison of the extended genotype, a shared database is needed.
Entities:
Keywords:
BRCA1; BRCA2; Germany; Hereditary breast cancer; Mutational spectrum
Authors: Christine Bekos; Christoph Grimm; Marlene Kranawetter; Stephan Polterauer; Felicitas Oberndorfer; Yen Tan; Leonhard Müllauer; Christian F Singer Journal: J Pers Med Date: 2021-06-24