Spectrum of genetic variants of BRCA1 and BRCA2 in a German single center study.
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).


CONCLUSIONS
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.
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Cornelia
C
Meisel
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Carolin Eva
CE
Sadowski
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Daniela
D
Kohlstedt
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Katja
K
Keller
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Franziska
F
Stäritz
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Nannette
N
Grübling
Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany.|Medical Genetic Center, Munich, Germany.
Kerstin
K
Becker
National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany.
Luisa
L
Mackenroth
National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany.
Andreas
A
Rump
National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute for Clinical Genetics, Technische Universität Dresden, Dresden, Germany.
Evelin
E
Schröck
Department of Obstetrics and Gynecology, University Hospital of Schleswig-Holstein, University Kiel, Kiel, Germany.
Norbert
N
Arnold
Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Pauline
P
Wimberger
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.|National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany. karin.kast@uniklinikum-dresden.de.|German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany. karin.kast@uniklinikum-dresden.de.
Karin
http://orcid.org/0000-0001-6531-755X
K
Kast
D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
BRCA1; BRCA2; Germany; Hereditary breast cancer; Mutational spectrum