Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach.

Autor:	Caputo SM; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France. Electronic address: sandrine.caputo@curie.fr., Golmard L; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Léone M; Service de Génétique, plate-forme mixte des cancers fréquents, Hospices Civils de Lyon, Bron 69229, France., Damiola F; Centre Léon Bérard, Lyon 69373, France., Guillaud-Bataille M; Service de Génétique des Tumeurs, Gustave Roussy, Villejuif 94806, France., Revillion F; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Rouleau E; Service de Génétique des Tumeurs, Gustave Roussy, Villejuif 94806, France., Derive N; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Buisson A; Service de Génétique, plate-forme mixte des cancers fréquents, Hospices Civils de Lyon, Bron 69229, France., Basset N; Département de génétique, AP-HP, Sorbonne université-Site Pitié-Salpêtrière, Paris 75013, France., Schwartz M; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Vilquin P; Département Pathologie et Oncobiologie, CHU Montpellier, Montpellier 34070, France., Garrec C; Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes 44093, France., Privat M; Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand 63000, France., Gay-Bellile M; Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand 63000, France; INSERM U1240, Université Clermont Auvergne, Clermont-Ferrand 63000, France., Abadie C; Unité d'Oncogénétique, Institut de Cancérologie de l'Ouest, Centre René Gauducheau, St Herbain-Nantes 44805, France., Abidallah K; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Airaud F; Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes 44093, France., Allary AS; Department of Cancer Biology, Laboratory of Molecular Oncogenetics, Institut Paoli Calmettes, Marseille 13273, France., Barouk-Simonet E; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Belotti M; Department of Genetics, Institut Curie, Paris 75005, France; Clinical research direction, Institut Curie, Paris 75005, France., Benigni C; Hôpital d'Enfants, CHRU Nancy Hopitaux de Brabois, Vandoeuvre les Nancy 54500, France., Benusiglio PR; UF d'Oncogénétique, GH Pitié-Salpêtrière, AP-HP, Sorbonne Université, Paris 75013, France., Berthemin C; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Berthet P; Oncogenetic, Department of Biopathology, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Bertrand O; Department of Genetics, Institut Curie, Saint-Cloud 92210, France., Bézieau S; Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes 44093, France., Bidart M; Laboratoire de Génétique Moléculaire: Maladies Héréditaires et Oncologie, CHU Grenoble Alpes, Grenoble 38700, France; INSERM 1209, Université Grenoble Alpes, Grenoble 38700, France., Bignon YJ; Department of Oncogenetics, Centre Jean Perrin, UMR INSERM 1240, Université Clermont Auvergne, Clermont-Ferrand Cedex 63011, France., Birot AM; Service de Génétique, Hôpital Européen Georges Pompidou, Paris 75015, France., Blanluet M; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Bloucard A; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Bombled J; Service de Génétique des Tumeurs, Gustave Roussy, Villejuif 94806, France., Bonadona V; Département Prévention Santé Publique, Centre Léon Bérard, Lyon 69008, France., Bonnet F; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Bonnet-Dupeyron MN; Consultations de Génétique, Centre Hospitalier de Valence, Valence 26953, France., Boulaire M; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Boulouard F; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Bouras A; Service de Génétique, plate-forme mixte des cancers fréquents, Hospices Civils de Lyon, Bron 69229, France., Bourdon V; Department of Cancer Biology, Laboratory of Molecular Oncogenetics, Institut Paoli Calmettes, Marseille 13273, France., Brahimi A; Department of Genetics, CHU Lille, Lille 59000, France., Brayotel F; Oncogenetics Laboratory, Institut Godinot, Reims 51726, France., Bressac de Paillerets B; Service de Génétique des Tumeurs, Gustave Roussy, Villejuif 94806, France., Bronnec N; Génétique Médicale, CHU Bordeaux, Bordeaux 33076, France., Bubien V; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Buecher B; Department of Genetics, Institut Curie, Paris 75005, France., Cabaret O; Service de Génétique des Tumeurs, Gustave Roussy, Villejuif 94806, France., Carriere J; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Chiesa J; Department of Genetics, Centre Hospitalier Régional Universitaire, Nimes 30029, France., Chieze-Valéro S; Service Oncogénétique Régional Poitou-Charentes, CH Georges Renon, Niort 79000, France., Cohen C; Service de Génétique, CHI de Poissy-Saint Germain En Laye, Poissy 78300, France., Cohen-Haguenauer O; Service de Génétique, CHI de Poissy-Saint Germain En Laye, Poissy 78300, France., Colas C; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Collonge-Rame MA; Oncobiologie Génétique Bioinformatique, CHRU Besançon, Besançon 25030, France., Conoy AL; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Coulet F; Département de génétique, AP-HP, Sorbonne université-Site Pitié-Salpêtrière, Paris 75013, France., Coupier I; Département Pathologie et Oncobiologie, CHU Montpellier, Montpellier 34070, France., Crivelli L; Centre Eugène Marquis, Rennes, France., Cusin V; Département de génétique, AP-HP, Sorbonne université-Site Pitié-Salpêtrière, Paris 75013, France., De Pauw A; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Dehainault C; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Delhomelle H; Department of Genetics, Institut Curie, Saint-Cloud 92210, France., Delnatte C; Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes 44093, France; Unité d'Oncogénétique, Institut de Cancérologie de l'Ouest, Centre René Gauducheau, St Herbain-Nantes 44805, France., Demontety S; Department of Genetics, Institut Curie, Paris 75005, France., Denizeau P; Centre Hospitalo-Universitaire Rennes, Rennes 35000, France., Devulder P; Oncogenetic, Department of Biopathology, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Dreyfus H; Institut Sainte Catherine, Avignon 84082, France., d'Enghein CD; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Dupré A; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Durlach A; Consultation oncogénétique, CHU Reims, Reims 51092, France., Dussart S; Département Prévention Santé Publique, Centre Léon Bérard, Lyon 69008, France., Fajac A; Service d'Anatomie et Cytologie Pathologiques, Hôpital Tenon, AP-HP, Sorbonne Université, Paris 75020, France., Fekairi S; Department of Cancer Biology, Laboratory of Molecular Oncogenetics, Institut Paoli Calmettes, Marseille 13273, France., Fert-Ferrer S; UF Consultation de génétique, Centre Hospitalier Métropole Savoie, Chambéry 73011, France., Fiévet A; Service de Génétique des Tumeurs, Gustave Roussy, Villejuif 94806, France., Fouillet R; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Mouret-Fourme E; Department of Genetics, Institut Curie, Saint-Cloud 92210, France., Gauthier-Villars M; Department of Genetics, Institut Curie, Paris 75005, France., Gesta P; Service Oncogénétique Régional Poitou-Charentes, CH Georges Renon, Niort 79000, France., Giraud S; Hospices Civils de Lyon, Lyon 69229, France., Gladieff L; Oncogenetics Department, Institut Claudius Regaud, Toulouse 31059, France., Goldbarg V; Gustave Roussy, Département de médecine oncologique, Villejuif 94805, France., Goussot V; Département de Biologie et Pathologie des Tumeurs, Centre Georges François Leclerc, Dijon 21000, France., Guibert V; Laboratoire de Génétique Moléculaire, Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes 44093, France., Guillerm E; Département de génétique, AP-HP, Sorbonne université-Site Pitié-Salpêtrière, Paris 75013, France., Guy C; Department of Genetics, Institut Curie, Paris 75005, France., Hardouin A; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Heude C; Oncogenetic, Department of Biopathology, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Houdayer C; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Ingster O; Département de Génétique Médicale/oncogénétique, CHU Angers, Angers 49000, France., Jacquot-Sawka C; Centre de Génétique, CHU de Dijon (hopital François Mitterand) and CLCC de Dijon (Centre Georges François Leclerc), Dijon 21000, France., Jones N; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Krieger S; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France; Inserm U1245, Rouen University, Normandy Centre for Genomic and Personalized Medicine, Rouen 76031, France., Lacoste S; Department of Genetics, Institut Curie, Paris 75005, France., Lallaoui H; CH La rochelle, La Rochelle 17000, France., Larbre H; Oncogenetics Laboratory, Institut Godinot, Reims 51726, France., Laugé A; Department of Genetics, Institut Curie, Paris 75005, France., Le Guyadec G; Laboratoire de Génétique Moléculaire: Maladies Héréditaires et Oncologie, CHU Grenoble Alpes, Grenoble 38700, France., Le Mentec M; Department of Genetics, Institut Curie, Paris 75005, France., Lecerf C; Department of Genetics, Institut Curie, Paris 75005, France., Le Gall J; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Legendre B; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Legrand C; Service de Génétique, CHU Grenoble Alpes, Grenoble 38700, France., Legros A; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Lejeune S; Department of Genetics, CHU Lille, Lille 59000, France., Lidereau R; Department of Genetics, Institut Curie, Paris 75005, France., Lignon N; Oncogenetics Department, Institut Claudius Regaud, Toulouse 31059, France., Limacher JM; Génétique Oncologique Clinique, Hospices Civils de Colmar, Colmar 68000, France., Doriane Livon; Department of Clinical Cancer Genetics, Institut Paoli-Calmettes, Marseille 13273, France., Lizard S; Department of Genetics, CHRU Nancy Hopitaux de Brabois, Vandoeuvre les Nancy 54500, France., Longy M; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Lortholary A; Department of Genetics, Hôpital Privé du Confluent, Nantes 44202, France., Macquere P; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Mailliez A; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Malsa S; Department of Genetics, CHU de Martinique, Fort de France 97200, Martinique., Margot H; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Mari V; Service oncogénétique, Centre Antoine Lacassagne, Nice 06189, France., Maugard C; Génétique Oncologique Moléculaire, Hôpital de Hautepierre, Strasbourg 67000, France., Meira C; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Menjard J; Department of Genetics, CHU Brest, Brest 29600, France., Molière D; Service de Génétique, Hôpital Européen Georges Pompidou, Paris 75015, France., Moncoutier V; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Moretta-Serra J; Department of Clinical Cancer Genetics, Institut Paoli-Calmettes, Marseille 13273, France., Muller E; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France; Inserm U1245, Rouen University, Normandy Centre for Genomic and Personalized Medicine, Rouen 76031, France., Nevière Z; Oncogenetic, Department of Biopathology, Comprehensive Cancer Center François Baclesse, Caen 14076, France., Nguyen Minh Tuan TV; Department of Genetics, Institut Curie, Paris 75005, France; Paris Sciences Lettres Research University, Paris 75005, France., Noguchi T; Department of Cancer Biology, Laboratory of Molecular Oncogenetics, Institut Paoli Calmettes, Marseille 13273, France., Noguès C; Department of Clinical Cancer Genetics, Institut Paoli-Calmettes, Marseille 13273, France., Oca F; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Popovici C; Department of Cancer Biology, Laboratory of Molecular Oncogenetics, Institut Paoli Calmettes, Marseille 13273, France., Prieur F; Service de Génétique, CHU St Etienne, Saint Etienne 42055, France., Raad S; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Rey JM; Département Pathologie et Oncobiologie, CHU Montpellier, Montpellier 34070, France., Ricou A; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France; Inserm U1245, Rouen University, Normandy Centre for Genomic and Personalized Medicine, Rouen 76031, France., Salle L; Service Oncogénétique Régional Poitou-Charentes, CH Georges Renon, Niort 79000, France., Saule C; Department of Genetics, Institut Curie, Saint-Cloud 92210, France., Sevenet N; Unité d'Oncogénétique, Institut Bergonié, Bordeaux 33076, France., Simaga F; Department of Genetics, Institut Curie, Paris 75005, France., Sobol H; Department of Cancer Biology, Laboratory of Molecular Oncogenetics, Institut Paoli Calmettes, Marseille 13273, France., Suybeng V; Department of Genetics, Institut Curie, Paris 75005, France., Tennevet I; Department of Genetics, Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, Rouen 76031, France; Department of Oncology, Comprehensive Cancer Centre Henri Becquerel, Normandy Centre for Genomic and Personalized Medicine, Rouen 76031, France., Tenreiro H; Department of Genetics, Institut Curie, Paris 75005, France., Tinat J; Génétique Médicale, CHU Bordeaux, Bordeaux 33076, France., Toulas C; Oncogenetics Laboratory, Institut Claudius Regaud, Toulouse 31059, France., Turbiez I; Clinical research direction, Institut Curie, Paris 75005, France., Uhrhammer N; Département d'Oncogénétique, Centre Jean Perrin, Clermont-Ferrand 63000, France; INSERM U1240, Université Clermont Auvergne, Clermont-Ferrand 63000, France., Vande Perre P; Oncogenetics Laboratory, Institut Claudius Regaud, Toulouse 31059, France., Vaur D; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France; Inserm U1245, Rouen University, Normandy Centre for Genomic and Personalized Medicine, Rouen 76031, France., Venat L; Department of oncology, CHU Dupuytren, Limoges 87042, France., Viellard N; Department of Genetics, Institut Curie, Paris 75005, France., Villy MC; Department of Genetics, Institut Curie, Paris 75005, France., Warcoin M; Department of Genetics, Institut Curie, Paris 75005, France., Yvard A; Department of Genetics, Hôpital Privé du Confluent, Nantes 44202, France., Zattara H; Department of Genetics, Centre Oscar Lambret, Lille 59000, France., Caron O; Gustave Roussy, Département de médecine oncologique, Villejuif 94805, France., Lasset C; Département Prévention Santé Publique, Centre Léon Bérard, Lyon 69008, France., Remenieras A; Department of Cancer Biology, Laboratory of Molecular Oncogenetics, Institut Paoli Calmettes, Marseille 13273, France., Boutry-Kryza N; Service de Génétique, plate-forme mixte des cancers fréquents, Hospices Civils de Lyon, Bron 69229, France., Castéra L; Laboratory of Cancer Biology and Genetics, Comprehensive Cancer Center François Baclesse, Caen 14076, France; Inserm U1245, Rouen University, Normandy Centre for Genomic and Personalized Medicine, Rouen 76031, France., Stoppa-Lyonnet D; Department of Genetics, Institut Curie, Paris 75005, France; Paris University, Paris 75005, France; INSERM U830, Institut Curie, Paris 75005, France.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2021 Oct 07; Vol. 108 (10), pp. 1907-1923. Date of Electronic Publication: 2021 Sep 30.
DOI:	10.1016/j.ajhg.2021.09.003
Abstrakt:	Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes. Competing Interests: Declaration of interests D.S.-L. and the Institut Curie have received honoraria for her participation in education meetings organized by AstraZeneca or Tesaro. The remaining authors declare no conflict of interest. (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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