| Title: |
A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2 |
| Authors: |
Zanti, Maria; O'Mahony, Denise G.; Parsons, Michael T.; Li, Hongyan; Dennis, Joe; Aittomäkkiki, Kristiina; Andrulis, Irene L.; Anton-Culver, Hoda; Aronson, Kristan J.; Augustinsson, Annelie; Becher, Heiko; Bojesen, Stig E.; Bolla, Manjeet K.; Brenner, Hermann; Brown, Melissa A.; Buys, Saundra S.; Canzian, Federico; Caputo, Sandrine M.; Castelao, Jose E.; Chang-Claude, Jenny; GC-HBOC study Collaborators; Czene, Kamila; Daly, Mary B.; De Nicolo, Arcangela; Devilee, Peter; Dörk, Thilo; Dunning, Alison M.; Dwek, Miriam; Eccles, Diana M.; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Gago-Dominguez, Manuela; García-Closas, Montserrat; García-Sáenz, José A.; Gentry-Maharaj, Aleksandra; Geurts - Giele, Willemina R. R.; Giles, Graham G.; Glendon, Gord; Goldberg, Mark S.; Gómez Garcia, Encarna B.; Güendert, Melanie; Guénel, Pascal; Hahnen, Eric; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Harkness, Elaine F.; Hogervorst, Frans B. L.; Hollestelle, Antoinette |
| Contributors: |
Cutting, Garry; AECC; Fundación Mutua Madrileña; Autonomous Government of Galicia; European Regional Development FEDER Funds; Spanish Instituto de Salud Carlos III; MRC Core Funding; National Institute for Health Research University College London Hospitals Biomedical Research Centre; Oak Foundation; Institute of Cancer Research; Lon V Smith Foundation; David F. and Margaret T. Grohne Family Foundation; Specialized Program of Research Excellence (SPORE) in Breast Cancer; Minister of Science and Higher Education; Vetenskapsrådet; Swedish Cancer Foundation; Susan G. Komen for the Cure; National University Health System; National University of Singapore; Ministry of Health -Singapore; NHS; UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Breast Cancer Campaign; 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; Biobanking and Biomolecular Resources Research Infrastructure; North Carolina University Cancer Research Fund; Komen Foundation; USA National Cancer Institute of the National Institutes of Health; Survey and Biospecimen Shared Resource; Kreftforeningen; South Eastern Norway Health Authority; Norges Forskningsråd; K.G. Jebsen Centre for Breast Cancer Research; Ministry of Economic Development, Innovation and Export Trade; Quebec Breast Cancer Foundation; Robert and Kate Niehaus Clinical Cancer Genetics Initiative; Berta Kamprad Foundation; Advanced grant; Australian National Health and Medical Research Council; Cancer Council Victoria; VicHealth; NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer; Hamburg Cancer Society; Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” MASA; Fonds Wetenschappelijk Onderzoek; Stichting Tegen Kanker; University of Eastern Finland; Finnish Cancer Organizations; Cancer Fund of North Savo; Special Government Funding (VTR) of Kuopio University Hospital; Märit and Hans Rausing’s Initiative Against Breast Cancer; Bert von Kantzows Foundation; Gustav V Jubilee Foundation; Swedish Cancer Society; Karolinska Institutet; Stockholm County Council; Government of Russian Federation; Russian Foundation for Basic Research; Hannover Medical School; Cancer Foundation Finland; Sigrid Juséliuksen Säätiö; Helsinki University Hospital Research Fund; Rudolf Bartling Foundation; Claudia von Schilling Foundation; Deutsche Krebshilfe; German Breast Group GmbH; Department of Internal Medicine, Johanniter GmbH Bonn, Johanniter Krankenhaus, Bonn, Germany; Institute of the Ruhr University Bochum; Institute for Prevention and Occupational Medicine of the German Social Accident Insurance; Robert Bosch Foundation; European Regional Development Fund and Free State of Saxony, Germany; NIHR Manchester Biomedical Research Centre; National Institute for Health Research; Baden Württemberg Ministry of Science, Research and Arts; Medical Research Council; ISCIII RETIC; Health Research Fund; Statistics Netherlands; World Cancer Research Fund; Dutch ZON; Dutch Prevention Funds; LK Research Funds; Netherlands Cancer Registry; Dutch Ministry of Public Health, Welfare and Sports; National Research Council; Associazione Italiana per la Ricerca sul Cancro; Stavros Niarchos Foundation; Hellenic Health Foundation; Bundesministerium für Bildung und Forschung; German Cancer Aid; Institut national de la santé et de la recherche médicale; Mutuelle Générale de l'Education Nationale; Institut Gustave-Roussy; Ligue Contre le Cancer; International Agency for Research on Cancer; European Commission; NCRN; Against Breast Cancer; Public Health Institute; University of Southern California; University of California, San Francisco; Centers for Disease Control and Prevention’s National Program of Cancer Registries; California Department of Public Health; National Cancer Institute of the National Institutes of Health; Herlev and Gentofte Hospital; Danish Medical Research Council; Chief Physician Johan Boserup and Lise Boserup Fund; Agence Nationale de la Recherche; Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail; Ligue Nationale contre le Cancer; Institut National Du Cancer; Fondation de France; University of Crete; Canadian Cancer Society; German Cancer Research Center; Helmholtz Society; Dietmar-Hopp Foundation; Ministerio de Economía y Competitividad; Fomento de la Investigación Clínica Independiente, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain; Consellería de Economía, Emprego e Industria, Xunta de Galicia; Xerencia de Xestion Integrada de Vigo-SERGAS, Instituto de Salud Carlos III; Programa Grupos Emergentes, Cancer Genetics Unit, Instituto de Investigacion Biomedica Galicia Sur; Acción Estratégica de Salud del Instituto de Salud Carlos III FIS Intrasalud; Acción Estratégica de Salud del Instituto de Salud Carlos III; Cancer Council Western Australia; Breast Cancer Now; ELAN-Fond of the University Hospital of Erlangen; National Institute of Environmental Health Sciences; National Breast Cancer Foundation; Cancer Institute NSW; Dutch Cancer Society; Victorian Breast Cancer Research Consortium; Victorian Health Promotion Foundation; New South Wales Cancer Council; National Health and Medical Research Council of Australia; National Cancer Institute; Canadian Institutes of Health Research; Department of Defence; Post-Cancer GWAS initiative; Seventh Framework Programme; Ministère de l'Économie, de la Science et de l'Innovation - Québec; Government of Canada; Cancer Research UK; National Institutes of Health; National Cancer Institute Intramural Research Program; Horizon 2020 Framework Programme; Telethon Cyprus; Australian National Health and Medical Research Funding; Research and Innovation Foundation; Breast Cancer Research Foundation; Ovarian Cancer Research Fund; Deutsches Krebsforschungszentrum |
| Source: |
Human Mutation ; volume 2023, page 1-17 ; ISSN 1098-1004 |
| Publisher Information: |
Wiley |
| Publication Year: |
2023 |
| Collection: |
Wiley Online Library (Open Access Articles via Crossref) |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1155/2023/9961341 |
| Availability: |
https://doi.org/10.1155/2023/9961341; http://downloads.hindawi.com/journals/humu/2023/9961341.pdf; http://downloads.hindawi.com/journals/humu/2023/9961341.xml |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.2CB9623A |
| Database: |
BASE |