PuSH - Publication Server of Helmholtz Zentrum München: A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to <em>BRCA1</em> and <em>BRCA2</em>.

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Zanti, M.* ; O'Mahony, D.G.* ; Parsons, M.T.* ; Li, H.* ; Dennis, J.* ; Aittomäkkiki, K.* ; Andrulis, I.L.* ; Anton-Culver, H.* ; Aronson, K.J.* ; Augustinsson, A.* ; Becher, H.* ; Bojesen, S.E.* ; Bolla, M.K.* ; Brenner, H.* ; Brown, M.A.* ; Buys, S.S.* ; Canzian, F.* ; Caputo, S.M.* ; Castelao, J.E.* ; Chang-Claude, J.* ; Czene, K.* ; Daly, M.B.* ; De Nicolo, A.* ; Devilee, P.* ; Dörk, T.* ; Dunning, A.M.* ; Dwek, M.* ; Eccles, D.M.* ; Engel, C.* ; Evans, D.G.* ; Fasching, P.A.* ; Gago-Dominguez, M.* ; Garcia-Closas, M.* ; García-Sáenz, J.A.* ; Gentry-Maharaj, A.* ; Geurts-Giele, W.R.R.* ; Giles, G.G.* ; Glendon, G.* ; Goldberg, M.S.* ; Garcia, E.B.G.* ; Gündert, M. ; Guénel, P.* ; Hahnen, E.* ; Haiman, C.A.* ; Hall, P.* ; Hamann, U.* ; Harkness, E.F.* ; Hogervorst, F.B.L.* ; Hollestelle, A.* ; Hoppe, R.* ; Hopper, J.L.* ; Houdayer, C.* ; Houlston, R.S.* ; Howell, A.* ; Investigators, A.* ; Jakimovska, M.* ; Jakubowska, A.* ; Jernström, H.* ; John, E.M.* ; Kaaks, R.* ; Kitahara, C.M.* ; Koutros, S.* ; Kraft, P.* ; Kristensen, V.N.* ; Lacey, J.V.* ; Lambrechts, D.* ; Leone, M.* ; Lindblom, A.* ; Lush, M.* ; Mannermaa, A.* ; Manoochehri, M.* ; Manoukian, S.* ; Margolin, S.* ; Martinez, M.E.* ; Menon, U.* ; Milne, R.L.* ; Monteiro, A.N.* ; Murphy, R.A.* ; Neuhausen, S.L.* ; Nevanlinna, H.* ; Newman, W.G.* ; Offit, K.* ; Park, S.K.* ; James, P.* ; Peterlongo, P.* ; Peto, J.* ; Plaseska-Karanfilska, D.* ; Punie, K.* ; Radice, P.* ; Rashid, M.U.* ; Rennert, G.* ; Romero, A.* ; Rosenberg, E.H.* ; Saloustros, E.* ; Sandler, D.P.* ; Schmidt, M.K.* ; Schmutzler, R.K.* ; Shu, X.* ; Simard, J.* ; Southey, M.C.* ; Stone, J.* ; Stoppa-Lyonnet, D.* ; Tamimi, R.M.* ; Tapper, W.J.* ; Taylor, J.A.* ; Teo, S.H.* ; Teras, L.R.* ; Terry, M.B.* ; Thomassen, M.* ; Troester, M.A.* ; Vachon, C.M.* ; Vega, A.* ; Vreeswijk, M.P.G.* ; Wang, Q.* ; Wappenschmidt, B.* ; Weinberg, C.R.* ; Wolk, A.* ; Zheng, W.* ; Feng, B.* ; Couch, F.J.* ; Spurdle, A.B.* ; Easton, D.F.* ; Goldgar, D.E.* ; Michailidou, K.*

A likelihood ratio approach for utilizing case-control data in the clinical classification of rare sequence variants: Application to BRCA1 and BRCA2.

Hum. Mutat. 2023:17 (2023)

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Abstract
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A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity-findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Breast-cancer; Ovarian-cancer; Risks; Association

ISSN (print) / ISBN 1059-7794

e-ISSN 1098-1004

Journal Human Mutation

Quellenangaben Volume: 2023, Article Number: 17

Publisher Wiley

Publishing Place Adam House, 3rd Fl, 1 Fitzroy Sq, London, Wit 5he, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes Research Type 1 (IDF)

Grants Royal Marsden/ICR NIHR Biomedical Research Centre
Institute of Cancer Research
Erasmus MC Family Cancer Clinic
Faculty of Medicine Tissue Bank
NBHS
Canada Research Chair in Oncogenetics
Swedish Medical Research Counsel
KARMA
Bochum, Germany
Heidelberg, Germany
Molecular Genetics of Breast Cancer
Centers for Disease Control and Prevention National Program of Cancer Registries
Medical Faculty of Mannheim
Blood bank Sanquin, The Netherlands
Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation
National Institute for Health Research University College London Hospitals Biomedical Research Centre
NIHR Biomedical Research Centre - Eve Appeal (The Oak Foundation)
NHS
Institute of Cancer Research (ICR), London
Breast Cancer Now
David F. and Margaret T. Grohne Family Foundation
DKFZ - Swedish Cancer Foundation
National University Health System, Singapore
NHS in the East of England through the Clinical Academic Reserve - Ministry of Health, Singapore, National University of Singapore
UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge
Intramural Research Program of the Division of Cancer Epidemiology and Genetics
Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics
Intramural Research Funds of the National Cancer Institute, Department of Health and Human Services, USA
North Carolina University Cancer Research Fund
USA National Cancer Institute of the National Institutes of Health - Komen Foundation
Northern California Breast Cancer Family Registry (NC-BCFR)
Norwegian Cancer Society
K.G. Jebsen Centre for Breast Cancer Research
Robert and Kate Niehaus Clinical Cancer Genetics Initiative
Cancer Council Victoria
Breast Cancer Research Foundation - Cancer Council Victoria
Italian Association for Cancer Research (AIRC)
Hamburg Cancer Society
Stichting tegen Kanker
University of Eastern Finland
Finnish Cancer Organizations
Cancer Fund of North Savo
special Government Funding (VTR) of Kuopio University Hospital
Marit and Hans Rausing's Initiative Against Breast Cancer
Bert von Kantzows foundation
Gustav V Jubilee foundation
Karolinska Institutet
Stockholm County Council
Russian Foundation for Basic Research
Friends of Hannover Medical School
Cancer Foundation Finland
Sigrid Juselius Foundation
Helsinki University Hospital Research Fund
Rudolf Bartling Foundation
Lower Saxonian Cancer Society
Claudia von Schilling Foundation for Breast Cancer Research
Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance
Deutsches Krebsforschungszentrum (DKFZ), Heidelberg
Robert Bosch Foundation
GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer)
NIHR
Baden Wurttemberg Ministry of Science, Research and Arts
Navarra, ISCIII RETIC
World Cancer Research Fund (WCRF), Statistics Netherlands (the Netherlands)
Dutch ZON (Zorg Onderzoek Nederland)
Dutch Prevention Funds
Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds
National Research Council (Italy)
Associazione Italiana per la Ricerca sul Cancro(AIRC), Italy
Stavros Niarchos Foundation (Greece)
Hellenic Health Foundation
Federal Ministry of Education and Research (BMBF) (Germany)
German Cancer Research Center (DKFZ)
Institut National de la Sante et de la Recherche Medicale (INSERM) (France)
Mutuelle Generale de l'Education Nationale
Institut Gustave Roussy
Ligue contre le Cancer
International Agency for Research on Cancer
European Commission (DG-SANCO)
NCRN
California Teachers Study (CTS)
American Cancer Society funds the creation, maintenance
Herlev and Gentofte Hospital
Danish Medical Research Council
Chief Physician Johan Boserup and Lise Boserup Fund
Agence nationale de la recherche (ANR)
Ligue Nationale contre le Cancer, Agence Nationale de Securite Sanitaire, de l'Alimentation, de l'Environnement et du Travail (ANSES)
Institut National du Cancer (INCa)
Fondation de France
University of Crete
Helmholtz Society
Dietmar-Hopp Foundation
Xunta de Galicia, Spain
Ministerio de Economía y Competitividad
Fomento de la Investigacion Clinica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain
Programa Grupos Emergentes
FEDER PI17/00918/Cofinanciado FEDER
Cancer Council Western Australia
National Cancer Research Network (NCRN) - National Health and Medical Research Council, Australia
NIHR Biomedical Research Centre
Breast Cancer Now and acknowledges NHS
ELAN-Fond of the University Hospital of Erlangen - Cancer Research UK
intramural research program of the National Institutes of Health
Cancer Institute NSW
Victorian Breast Cancer Research Consortium
Victorian Health Promotion Foundation (Australia)
New South Wales Cancer Council
National Health and Medical Research Council of Australia
National Cancer Institute (USA)
Breast Cancer Research Foundation
Komen Foundation for the Cure
Canadian Institutes of Health Research (CIHR)
Government of Canada through Genome Canada
National Cancer Institute intramural research program
Quebec Breast Cancer Foundation
Ministere de l'Economie et de l'Innovation du Quebec through Genome Quebec
Government of Canada through the Genome Canada
BCAC