Evidence map›Paper›PMID 31131967›Full record

ArticleHuman mutation2019

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Michael T Parsons, Emma Tudini, Hongyan Li, Eric Hahnen, Barbara Wappenschmidt, Lidia Feliubadaló, Cora M Aalfs, Simona Agata, Kristiina Aittomäki, Elisa Alducci and 211 more

Registry-linked trialAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human mutation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01689584 (Study of Family COsegregation of Nucleotide VARiants in the Panel of Genes to Validate Their Use in Genetic Counseling), which is not on this map. Cited by 107 papers.

0numbers the graph read from it
0cells of the map it votes in
107citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT01689584 narecruitingnot on this map

Study of Family COsegregation of Nucleotide VARiants in the Panel of Genes to Validate Their Use in Genetic Counseling

TypeinterventionalSponsorInstitut CurieRan2012 to 2038Enrolled11,000ConditionsGene Mutation-Related Cancer, Genetic PredispositionArmssalivary kit
3 · Its place in the literature

Who cites it

107 citing papers in PubMed.

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  12. Advances in Systemic Therapy for Ovarian Cancer Over the Past Decade: A Clinical and Molecular Perspective.Medical science monitor : international medical journal of experimental and clinical research · 2025
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  18. Reclassification of VUS inGenetics in medicine open · 2025
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47 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

221 authors.

Michael T ParsonsDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.ORCID 0000-0003-3242-8477
Emma TudiniDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Hongyan LiCancer Control and Population Science, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Eric HahnenCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Barbara WappenschmidtCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Lidia FeliubadalóHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Cora M AalfsDepartment of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.
Simona AgataImmunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy.
Kristiina AittomäkiDepartment of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Elisa AlducciImmunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy.
María Concepción Alonso-CerezoClinical Genetics, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria, Madrid, Spain.
Norbert ArnoldDepartment of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
Bernd AuberInstitute of Human Genetics, Hannover Medical School, Hannover, Germany.
Rachel AustinGenetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.
Jacopo AzzolliniUnit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Judith BalmañaHigh Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Elena BarbieriDepartment of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
Claus R BartramInstitute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
Ana BlancoFundación Pública galega Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.
Britta BlümckeCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Sandra BonacheOncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Bernardo BonanniDivision of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Åke BorgDivision of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Beatrice BortesiDivision of Oncology, University Hospital of Parma, Parma, Italy.
Joan BrunetHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Carla BruzzoneUnit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Karolin BuckschInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Giulia CagnoliUnit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Trinidad CaldésMolecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
Almuth CaliebeInstitute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
Maria A CaligoSOD Genetica Molecolare, University Hospital, Pisa, Italy.
Mariarosaria CalvelloDivision of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Gabriele L CaponeDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
Sandrine M CaputoService de Génétique, Institut Curie, Paris, France.
Ileana CarnevaliUO Anatomia Patologica, Ospedale di Circolo ASST Settelaghi, Varese, Italy.
Estela CarrascoHigh Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Virginie Caux-MoncoutierService de Génétique, Institut Curie, Paris, France.
Pietro CavalliServizio di Genetica, ASST di Cremona, Cremona, Italy.
Giulia CiniDivision of Functional Onco-genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
Edward M ClarkeDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Paola ConcolinoFondazione Policlinico Universitario A.Gemelli, IRCCS, Rome, Italy.
Elisa J CopsParkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
Laura CortesiDepartment of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
Fergus J CouchDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Esther DarderHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Miguel de la HoyaMolecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.ORCID 0000-0002-8113-1410
Michael DeanLaboratory of Translational Genomics, DCEG, National Cancer Institute, Gaithersburg, Maryland.
Irmgard DebatinInstitute of Human Genetics, University Hospital Ulm, Ulm, Germany.
Jesús Del ValleHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Capucine DelnatteLaboratoire de Genetique Moleculaire, CHU Nantes, Nantes, France.
Nicolas DeriveService de Génétique, Institut Curie, Paris, France.
Orland DiezOncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.ORCID 0000-0001-7339-0570
Nina DitschDepartment of Gynecology and Obstetrics, University of Munich, Munich, Germany.
Susan M DomchekBasser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Véronique DutrannoyInstitute of Medical and Human Genetics, Charité -Universitätsmedizin Berlin, Berlin, Germany.
Diana M EcclesFaculty of Medicine, University of Southampton, Southampton, UK.ORCID 0000-0002-9935-3169
Hans EhrencronaDepartment of Clinical Genetics and Pathology, Laboratory Medicine, Office for Medical Services - Region Skåne, Lund, Sweden.
Ute EndersInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
D Gareth EvansGenomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
Chantal FarraMedical Genetics, American University of Beirut Medical Center, Beirut, Lebanon.
Ulrike FaustInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Ute FelborInstitute of Human Genetics, University Medicine Greifswald, Greifswald, Germany.
Irene FeroceDivision of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Miriam FineAdult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia.
William D FoulkesProgram in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
Henrique C R GalvaoOncogenetics Department, Barretos Cancer Hospital, São Paulo, Brazil.
Gaetana GambinoSOD Genetica Molecolare, University Hospital, Pisa, Italy.
Andrea GehrigDepartment of Human Genetics, University of Würzburg, Würzburg, Germany.
Francesca GensiniDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
Anne-Marie GerdesDepartment of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Aldo GermaniDepartment of Clinical and Molecular Medicine, Sant'Andrea University Hospital, Sapienza University, Rome, Italy.
Jutta GieseckeCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Viviana GismondiUnit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Carolina GómezHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Encarna B Gómez GarciaDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
Sara GonzálezHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Elia GrauHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Sabine GrillDivision of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen, Universität München, Munich, Germany.
Eva GrossDepartment of Gynecology and Obstetrics, University of Munich, Munich, Germany.
Aliana Guerrieri-GonzagaDivision of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Marine Guillaud-BatailleDepartement de Biopathologie, Gustave Roussy, Universite Paris-Saclay, Villejuif, France.
Sara Gutiérrez-EnríquezOncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.ORCID 0000-0002-1711-6101
Thomas HaafDepartment of Human Genetics, University of Würzburg, Würzburg, Germany.
Karl HackmannInstitute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
Thomas V O HansenDepartment of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Marion HarrisFamilial Cancer Centre, Monash Health, Clayton, Australia.
Jan HaukeCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Tilman HeinrichInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Heide HellebrandDivision of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen, Universität München, Munich, Germany.
Karen N HeroldThe City of Hope, Duarte, California.
Ellen HonischDepartment of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Judit HorvathInstitute of Human Genetics, University of Münster, Münster, Germany.
Claude HoudayerDepartment of Genetics, F76000 and Normandy University, UNIROUEN, Inserm U1245, Normandy Centre for Genomic and Personalized Medicine, Rouen University Hospital, Rouen, France.
Verena HübbelCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Silvia IglesiasHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Angel IzquierdoHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Paul A JamesParkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
Linda A M JanssenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Udo JeschkeDepartment of Gynecology and Obstetrics, University of Munich, Munich, Germany.
Silke KaulfußInstitute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Katharina KeuppCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Marion KiechleDivision of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen, Universität München, Munich, Germany.
Alexandra KölblDepartment of Gynecology and Obstetrics, University of Munich, Munich, Germany.
Sophie KriegerLaboratoire de Biologie Clinique et Oncologique, Centre Francois Baclesse, Caen, France.
Torben A KruseDepartment of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
Anders KvistDivision of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Fiona LallooGenomic Medicine, North West Genomics hub, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.
Mirjam LarsenCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Vanessa L LattimoreDepartment of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
Charlotte LautrupDepartment of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
Susanne LedigInstitute of Human Genetics, University of Münster, Münster, Germany.
Elena LeinertDepartment of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
Alexandra L LewisPeter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Joanna LimBreast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
Markus LoefflerInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Adrià López-FernándezHigh Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Emanuela Lucci-CordiscoUOC Genetica Medica, Fondazione Policlinico Universitario A.Gemelli IRCCS and Istituto di Medicina Genomica, Università Cattolica del Sacro Cuore, Rome, Italy.
Nicolai MaassDepartment of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
Siranoush ManoukianUnit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Monica MarabelliDivision of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan, Italy.
Laura MatricardiImmunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy.
Alfons MeindlDepartment of Gynecology and Obstetrics, University of Munich, Munich, Germany.
Rodrigo D MichelliOncogenetics Department, Barretos Cancer Hospital, São Paulo, Brazil.
Setareh MoghadasiDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Alejandro Moles-FernándezOncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Marco MontagnaImmunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy.
Gemma MontalbanOncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
Alvaro N MonteiroDepartment of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
Eva MontesHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Luigi MoriDepartment of Clinical and Experimental Science, University of Brescia c/o 2nd Internal Medicine, Hospital of Brescia, Brescia, Italy.
Lidia MoserleImmunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy.
Clemens R MüllerDepartment of Human Genetics, University of Würzburg, Würzburg, Germany.
Christoph MundhenkeDepartment of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
Nadia NaldiDivision of Oncology, University Hospital of Parma, Parma, Italy.
Katherine L NathansonBasser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
Matilde NavarroHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Heli NevanlinnaDepartment of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Cassandra B NicholsGenetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
Dieter NiederacherDepartment of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Henriette R NielsenDepartment of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
Kai-Ren OngWest Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, UK.
Nicholas PachterGenetic Services of Western Australia, King Edward Memorial Hospital, Perth, Australia.
Edenir I PalmeroMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil.
Laura PapiDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
Inge Sokilde PedersenClinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
Bernard PeisselUnit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Pedro Perez-SeguraMolecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
Katharina PfeiferDivision of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen, Universität München, Munich, Germany.
Marta PinedaHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Esther Pohl-RescignoCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Nicola K PoplawskiAdult Genetics Unit, Royal Adelaide Hospital, Adelaide, Australia.
Berardino PorfirioDepartment of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, University of Florence, Florence, Italy.
Anne S QuanteDivision of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen, Universität München, Munich, Germany.
Juliane RamserDivision of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen, Universität München, Munich, Germany.
Rui M ReisMolecular Oncology Research Center, Barretos Cancer Hospital, São Paulo, Brazil.
Françoise RevillionLaboratoire d'Oncogenetique Moleculaire Humaine, Centre Oscar Lambret, Lille, France.
Kerstin RhiemCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Barbara RiboliServizio di Genetica, ASST di Cremona, Cremona, Italy.
Julia RitterInstitute of Medical and Human Genetics, Charité -Universitätsmedizin Berlin, Berlin, Germany.
Daniela RiveraUnit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Paula RofesHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Andreas RumpInstitute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.
Monica SalinasHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Ana María Sánchez de AbajoServicio de Análisis Clínicos y Bioquímica Clínica, Complejo Hospitalario, Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaría, Spain.
Gunnar SchmidtInstitute of Human Genetics, Hannover Medical School, Hannover, Germany.
Ulrike SchoenwieseInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Jochen SeggewißInstitute of Human Genetics, University of Münster, Münster, Germany.
Ares SolanesHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Doris SteinemannInstitute of Human Genetics, Hannover Medical School, Hannover, Germany.
Mathias StillerInstitute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
Dominique Stoppa-LyonnetService de Génétique, Institut Curie, Paris, France.
Kelly J SullivanGenetic Health Service NZ- Northern Hub, Auckland District Health Board, Auckland, New Zealand.
Rachel SusmanGenetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.ORCID 0000-0002-3682-0620
Christian SutterInstitute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
Sean V TavtigianDepartment of Oncological Services, University of Utah School of Medicine, Salt Lake City, Utah.ORCID 0000-0002-7543-8221
Soo H TeoBreast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
Alex TeuléHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Mads ThomassenDepartment of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
Maria Grazia TibilettiUO Anatomia Patologica, Ospedale di Circolo ASST Settelaghi, Varese, Italy.
Marc TischkowitzDepartment of Medical Genetics, University of Cambridge, Cambridge, UK.
Silvia TognazzoImmunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV, IRCCS, Padua, Italy.
Amanda E TolandDepartment of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio.ORCID 0000-0002-0271-1792
Eva TorneroHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Therese TörngrenDivision of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Sara Torres-EsquiusHigh Risk and Cancer Prevention Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
Angela TossDepartment of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.ORCID 0000-0002-1854-6701
Alison H TrainerParkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
Katherine M TuckerPrince of Wales Clinical School, University of NSW, Sydney, New South Wales, Australia.
Christi J van AsperenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Marion T van MackelenberghDepartment of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
Liliana VarescoUnit of Hereditary Cancer, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Gardenia Vargas-ParraHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Raymonda VaronInstitute of Medical and Human Genetics, Charité -Universitätsmedizin Berlin, Berlin, Germany.
Ana VegaFundación Pública galega Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.ORCID 0000-0002-7416-5137
Ángela VelascoHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Anne-Sophie VesperDepartment of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Alessandra VielDivision of Functional Onco-genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
Maaike P G VreeswijkDepartment of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.ORCID 0000-0003-4068-9271
Sebastian A WagnerDepartment of Medicine, Hematology/Oncology, Goethe-University Frankfurt, Frankfurt, Germany.
Anke WahaCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Logan C WalkerDepartment of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand.
Rhiannon J WaltersDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Shan Wang-GohrkeDepartment of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
Bernhard H F WeberInstitute of Human Genetics, University Regensburg, Regensberg, Germany.
Wilko WeichertInstitute of Pathology, Technische Universität München, Munich, Germany.
Kerstin WielandInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Lisa WiesmüllerDepartment of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
Isabell WitzelDepartment of Gynecology, University Medical Center Hamburg, Hamburg, Germany.
Achim WöckelDepartment of Gynecology and Obstetrics, University Hospital Würzburg, Würzburg, Germany.
Emma R WoodwardGenomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, Manchester Academic Health Science Centre, Manchester Universities Foundation Trust, St. Mary's Hospital, Manchester, UK.ORCID 0000-0002-6297-2855
Silke ZachariaeInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Valentina ZampigaBiosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
Christine Zeder-GößDepartment of Gynecology and Obstetrics, University of Munich, Munich, Germany.
KConFab InvestigatorsSir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
Conxi LázaroHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
Arcangela De NicoloCancer Genomics Program, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Paolo RadiceUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.ORCID 0000-0001-6298-4111
Christoph EngelInstitute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
Rita K SchmutzlerCenter for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
David E GoldgarDepartment of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
Amanda B SpurdleDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.ORCID 0000-0003-1337-7897

Funding

The Role of CHFR in Tumorigenesis and Paclitaxel-Sensitivity in Breast CancerP50CA116201 · NCI · MAYO CLINIC ROCHESTER · PI PETER C LUCAS · 2005 to 2026
$49.9M
Epidemiologic StudiesU19CA148065 · NCI · HARVARD SCHOOL OF PUBLIC HEALTH · PI AHSAN, HABIBUL, BRUGGE, JOAN SIEFERT · 2010 to 2014
$10.6M
Epidemiological and Clinical Translational Studies Post Genome-Wide AssociationU19CA148537 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI EASTON, DOUGLAS FREDERICK, EELES, ROSALIND · 2010 to 2014
$10.4M
Ovarian cancer GWAS discovery, expansion and replication (N2 - Project #1)U19CA148112 · NCI · H. LEE MOFFITT CANCER CTR & RES INST · PI SELLERS, THOMAS A · 2010 to 2014
$10.2M
Risk and penetrance of mutations from breast cancer testing panels.R01CA192393 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH, NATHANSON, KATHERINE L. · 2014 to 2018
$6.3M
COMMON AND RARE SEQUENCE VARIANTS IN BREAST CANCER RISKR01CA121245 · NCI · UNIVERSITY OF UTAH · PI TAVTIGIAN, SEAN VAHRAM · 2007 to 2021
$4.9M
A genome-wide association study for breast cancer in BRCA1 mutation carriersR01CA128978 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH · 2008 to 2012
$4.8M
BRCA2 missense mutations and breast cancerR01CA116167 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH · 2007 to 2011
$3.0M
BRCA1 and BRCA2 missense mutations and breast cancer riskU01CA116167 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH · 2013 to 2017
$2.7M
Cancer Research UK C12292/A11174Cancer Research UK C1281/A12014Cancer Research UK C1287/A10118Cancer Research UK C1287/A10710Cancer Research UK C1287/A16563Cancer Research UK C5047/A10692Cancer Research UK C5047/A15007Cancer Research UK C5047/A8384Cancer Research UK C8197/A16565NCI NIH HHS P50 CA116201NCI NIH HHS R01 CA116167NCI NIH HHS R01 CA121245NCI NIH HHS R01 CA128978NCI NIH HHS R01 CA192393NCI NIH HHS U01 CA116167NCI NIH HHS U19 CA148065NCI NIH HHS U19 CA148112NCI NIH HHS U19 CA148537Wellcome Trust 203477/Z/16/Z
6 · The paper itself

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Indexed as

Mutation, MissenseAlternative SplicingBRCA1 ProteinBRCA2 ProteinComputational BiologyEarly Detection of CancerFemaleGenetic Predisposition to DiseaseHumansLikelihood FunctionsMaleMultifactorial InheritanceNeoplasmsBRCA1 ProteinBRCA1 protein, humanBRCA2 ProteinBRCA2 protein, humanBRCA1BRCA2classificationclinicalmultifactorialquantitativeuncertain significancevariant

Identifiers

PMID31131967
PMCPMC6772163

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.