Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.
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Abstract
FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658 was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.
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Peer reviewed: True
Funder: Fondazione Umberto Veronesi to Gisella Figlioli
Funder: Government of Canada
Funder: Canadian Institutes of Health Research, the Ministère de l’Économie et de l’Innovation du Québec
Funder: National Cancer Institute Intramural Research Program, National Institutes of Health
Funder: Dutch Ministry of Health, Welfare and Sport
Funder: ELAN-Fond of the University Hospital of Erlangen
Funder: NIHR Comprehensive Biomedical Research Centre, Guy’s & St. Thomas’ NHS Foundation Trust
Funder: King’s College London
Funder: Oxford Biomedical Research Centre
Funder: Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur. Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III, Spain
Funder: Dietmar-Hopp Foundation
Funder: Helmholtz Society
Funder: German Cancer Research Center (DKFZ)
Funder: University of Crete
Funder: Fondation de France
Funder: Institut National du Cancer (INCa)
Funder: Ligue Nationale contre le Cancer
Funder: Agence Nationale de Sécurité Sanitaire, de l’Alimentation, de l’Environnement et du Travail (ANSES)
Funder: Agence Nationale de la Recherche (ANR)
Funder: Chief Physician Johan Boserup and Lise Boserup Fund
Funder: Danish Medical Research Council
Funder: Herlev and Gentofte Hospital
Funder: Instituto de Salud Carlos III, the Red Temática de Investigación Cooperativa en Cáncer
Funder: Robert Bosch Foundation, Stuttgart
Funder: Deutsches Krebsforschungszentrum (DKFZ), Heidelberg
Funder: Institute for Prevention and Occupational Medicine of the German Social Accident Insurance
Funder: Institute of the Ruhr University Bochum (IPA), Bochum
Funder: Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany
Funder: Lower Saxonian Cancer Society
Funder: Claudia von Schilling Foundation for Breast Cancer Research
Funder: Rudolf Bartling Foundation
Funder: Helsinki University Hospital Research Fund
Funder: Sigrid Juselius Foundation
Funder: Cancer Foundation Finland
Funder: Friends of Hannover Medical School
Funder: Stockholm County Council
Funder: Karolinska Institutet
Funder: Swedish Cancer Society
Funder: The Gustav V Jubilee foundation
Funder: Bert von Kantzows foundation
Funder: Märit and Hans Rausings Initiative Against Breast Cancer
Funder: Kuopio University Hospital
Funder: Cancer Fund of North Savo
Funder: Finnish Cancer Organizations
Funder: University of Eastern Finland
Funder: National Breast Cancer Foundation
Funder: National Health and Medical Research Council (NHMRC)
Funder: Queensland Cancer Fund
Funder: Cancer Councils of New South Wales, Victoria, Tasmania and South Australia
Funder: Cancer Foundation of Western Australia
Funder: Cancer Council Victoria
Funder: Cancer Council New South Wales
Funder: Cancer Council South Australia
Funder: Cancer Council Tasmania
Funder: Hamburg Cancer Society
Funder: Cyprus Institute of Neurology and Genetics
Funder: Italian Association for Cancer Research (AIRC)
Funder: VicHealth
Funder: K.G. Jebsen Centre for Breast Cancer Research
Funder: Norwegian Cancer Society
Funder: Survey and Biospecimen Shared Resource
Funder: National Cancer Institute, Department of Health and Human Services, USA
Funder: Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics
Funder: Intramural Research Program of the Division of Cancer Epidemiology and Genetics
Funder: Division of Cancer Prevention, National Cancer Institute, National Institutes of Health
Funder: Agency for Science, Technology and Research of Singapore (A*STAR)
Funder: Susan G. Komen Breast Cancer Foundation
Funder: UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
Funder: NHS in the East of England
Funder: Women’s Cancer Center at the Huntsman Cancer Institute (HCI)
Funder: Utah Population Database (UPDB)
Funder: Utah Cancer Registry (UCR)
Funder: University of Utah HCI
Funder: Huntsman Cancer Foundation
Funder: University of Utah
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European Commission Horizon 2020 (H2020) Societal Challenges (634935)
Wellcome Trust (203477/Z/16/Z)
Cancer Research Uk (None)
Cancer Research Uk (None)