COsegregation of VARiants in Panel of Genes

NCT01689584 | Recruiting

• 1 other identifier: IC 2011-11
• Study Type: interventional
• Target: 11,000
• Locations: 5 countries
• Sites: 62

Brief Summary

The aim of the COVAR project is to achieve reliable classification of as many variants of interest as possible from the French OncoGenetics Database (FrOG, https://frog-db.fr/) in order to use them for the genetic counseling. The results obtained through this study will have a major impact on clinical management of the patients and their families conducting in some cases to propose a prophylactic surgery.

Conditions

Gene Mutation-Related Cancer; Genetic Predisposition

Keywords

BRCA1; BRCA2; VUS; co-segregation; genetic counseling; PALB2; panel of genes; variant; hypomorphic; Hereditary cancer (breast, ovarian, prostate, pancreas, digestive track)

Outcome Measures

Primary Outcomes (1)

• Perform the co-segregation analysis of the selected VUS (class 3) or likely pathogenic variant (class 4) in the families.

  Number of variants classified using methods based on likelihood ratio estimation of the selected VUS (class 3) or likely pathogenic variant (class 4) in the families in order to classify the maximum of variants in terms of their probability to be pathogenic (class 5) or (likely) benign (class 1 and 2).

  up to 15 years

Secondary Outcomes (3)

• Propose a standardized method to classify as many variants as possible from the national of the Genetics and Cancer Group (GGC) of Unicancer.

  up to 15 years

• Maximize the number of VUS (class 3) or likely pathogene (class 4) having associated recommendations for clinical management of at-risk relatives that can be used to guide genetic counselling.

  up to 15 years

• Assess the penetrance of selected variants of interest, particularly hypomorphic pathogenic variant (hypomorphic class 5) shared across multiple families.

  up to 15 years

Study Arms (1)

Covar

OTHER

Genetic: salivary kit

Interventions

salivary kit GENETIC

The saliva samples will be made of selected related (DNA).

Covar

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Index cases:
• A person carrying a variant of interest in a gene analyzed in a diagnostic setting by one of the laboratories within the Genetics and Cancer Group (GGC)-Unicancer network, classified as class 3, 4 or hypomorphic class 5, and selected by the national expert group for the gene concerned.
• Age ≥ 18 years.
• Signed written inform consent "index case"
• Related parties:
• Any relative of an index case with cancer
• Any relative without cancer related to an index case, selected by the investigators, according to family structure and degree of related compared to the index case
• For class 4 and hypomorphic class 5 variants; relatives currently undergoing analysis or having already obtained a test result for the variant of interest as part of clinical care.
• Age ≥ 18 years
• Information and signature of the informed consent "selected relatives"

You may not qualify if:

• Minors
• Persons deprived of liberty or under guardianship (including curators).
• Absence of signed written inform consent

Sponsors & Collaborators

• Institut Curie: lead

Study Sites (62)

Centre Hospitalier de Bastia

Bastia, Corsica, 20604, France

NOT YET RECRUITING

Institut Curie - Saint-Cloud site

Saint-Cloud, Haut de Seine, 92210, France

RECRUITING

CHU Amiens - Hôpital Nord

Amiens, 80054, France

RECRUITING

ICO - Centre Paul Papin

Angers, 49933, France

RECRUITING

Centre Hospitalier d'Angoulème

Angoulême, 16959, France

RECRUITING

Institut Sainte-Catherine

Avignon, 84918, France

RECRUITING

CHU Besançon

Besançon, 25030, France

RECRUITING

Groupe Hospitalier Pellegrin

Bordeaux, 33076, France

RECRUITING

Institut Bergonié

Bordeaux, 33076, France

RECRUITING

Centre Hospitalier Jacques Coeur

Bourges, 18020, France

RECRUITING

CHU Morvan de Brest

Brest, 29200, France

RECRUITING

Centre François Baclesse

Caen, 14076, France

RECRUITING

Centre Hospitalier Hôtel Dieu

Chambéry, 73011, France

RECRUITING

Centre Jean Perrin

Clermont-Ferrand, 63011, France

RECRUITING

Hôpital Civil de Colmar

Colmar, 68024, France

NOT YET RECRUITING

CHU de Dijon

Dijon, 21079, France

RECRUITING

CHU de Grenoble

Grenoble, 38043, France

RECRUITING

CHD Vendée

La Roche-sur-Yon, 85925, France

NOT YET RECRUITING

Groupe Hospitalier La Rochelle-Ré-Aunis

La Rochelle, 17019, France

RECRUITING

Hôpital Flaubert

Le Havre, 76083, France

RECRUITING

Centre Oscar Lambret

Lille, 59000, France

RECRUITING

Chru Lille

Lille, 59037, France

RECRUITING

CHU Dupuytren

Limoges, 87042, France

RECRUITING

Hospices Civils de Lyon

Lyon, 69229, France

RECRUITING

Centre Léon Bérard

Lyon, 69373, France

RECRUITING

Institut Paoli Calmettes

Marseille, 13009, France

RECRUITING

CHU La Timone

Marseille, 13385, France

RECRUITING

CHU Arnaud de Villeneuve

Montpellier, 34295, France

RECRUITING

Centre Catherine de Sienne

Nantes, 44202, France

RECRUITING

Centre Antoine Lacassagne

Nice, 06189, France

RECRUITING

Centre Hospitalier Georges Renon

Niort, 79021, France

RECRUITING

CHRU Caremeau

Nîmes, 30029, France

RECRUITING

Hôpital de la Source

Orléans, 45067, France

RECRUITING

Hôpital Saint-Antoine

Paris, 75012, France

RECRUITING

Groupe Hospitalier Pitié-Salpêtrière

Paris, 75013, France

RECRUITING

Hôpital Tenon

Paris, 75020, France

RECRUITING

Hôpital Saint-Louis

Paris, 75475, France

RECRUITING

HEGP

Paris, 75908, France

RECRUITING

Centre Hospitalier Intercommunal Poissy -Saint Germain-en-Laye

Poissy, 78303, France

NOT YET RECRUITING

CHU La Milétrie

Poitiers, 86021, France

RECRUITING

CHU de Reims

Reims, 51092, France

RECRUITING

ICC Courlancy

Reims, 51100, France

RECRUITING

Institut Jean Godinot

Reims, 51100, France

RECRUITING

Centre Eugène Marquis

Rennes, 35042, France

RECRUITING

CHU Rennes - Hôpital Sud

Rennes, 35203, France

NOT YET RECRUITING

CHU de Rouen

Rouen, 76031, France

RECRUITING

CHU Saint Etienne

Saint-Etienne, 42055, France

RECRUITING

ICO - Centre René Gauducheau

Saint-Herblain, 44804, France

RECRUITING

CLCC Paul Strauss

Strasbourg, 67033, France

RECRUITING

Hopital de Hautepierre - Hôpital Universitaire

Strasbourg, 67200, France

RECRUITING

Institut Claudius Regaud - IUCT - Oncopole

Toulouse, 31059, France

RECRUITING

CHU Bretonneau

Tours, 37044, France

RECRUITING

CH Simone VEIL

Troyes, 10003, France

RECRUITING

Centre Hospitalier de Valence

Valence, 26953, France

RECRUITING

Centre Alexis Vautrin

Vandœuvre-lès-Nancy, 54511, France

WITHDRAWN

CHU Nancy - Hôpital Brabois

Vandœuvre-lès-Nancy, 54511, France

RECRUITING

Gustave Roussy

Villejuif, 94805, France

RECRUITING

Institut Curie - Paris site

Paris, Île-de-France Region, 75005, France

RECRUITING

CHU de Pointe à Pitre

Pointe-à-Pitre, 97110, Guadeloupe

RECRUITING

CHU de Fort de France

Fort-de-France, 97261, Martinique

RECRUITING

Centre Hospitalier Territorial Gaston Bourret

Noumea, 98849, New Caledonia

NOT YET RECRUITING

CHU Sud Réunion Saint-Pierre

Saint-Pierre, 97410, Reunion

RECRUITING

Related Publications (8)

• Caputo SM, Golmard L, Leone M, Damiola F, Guillaud-Bataille M, Revillion F, Rouleau E, Derive N, Buisson A, Basset N, Schwartz M, Vilquin P, Garrec C, Privat M, Gay-Bellile M, Abadie C, Abidallah K, Airaud F, Allary AS, Barouk-Simonet E, Belotti M, Benigni C, Benusiglio PR, Berthemin C, Berthet P, Bertrand O, Bezieau S, Bidart M, Bignon YJ, Birot AM, Blanluet M, Bloucard A, Bombled J, Bonadona V, Bonnet F, Bonnet-Dupeyron MN, Boulaire M, Boulouard F, Bouras A, Bourdon V, Brahimi A, Brayotel F, Bressac de Paillerets B, Bronnec N, Bubien V, Buecher B, Cabaret O, Carriere J, Chiesa J, Chieze-Valero S, Cohen C, Cohen-Haguenauer O, Colas C, Collonge-Rame MA, Conoy AL, Coulet F, Coupier I, Crivelli L, Cusin V, De Pauw A, Dehainault C, Delhomelle H, Delnatte C, Demontety S, Denizeau P, Devulder P, Dreyfus H, d'Enghein CD, Dupre A, Durlach A, Dussart S, Fajac A, Fekairi S, Fert-Ferrer S, Fievet A, Fouillet R, Mouret-Fourme E, Gauthier-Villars M, Gesta P, Giraud S, Gladieff L, Goldbarg V, Goussot V, Guibert V, Guillerm E, Guy C, Hardouin A, Heude C, Houdayer C, Ingster O, Jacquot-Sawka C, Jones N, Krieger S, Lacoste S, Lallaoui H, Larbre H, Lauge A, Le Guyadec G, Le Mentec M, Lecerf C, Le Gall J, Legendre B, Legrand C, Legros A, Lejeune S, Lidereau R, Lignon N, Limacher JM, Doriane Livon, Lizard S, Longy M, Lortholary A, Macquere P, Mailliez A, Malsa S, Margot H, Mari V, Maugard C, Meira C, Menjard J, Moliere D, Moncoutier V, Moretta-Serra J, Muller E, Neviere Z, Nguyen Minh Tuan TV, Noguchi T, Nogues C, Oca F, Popovici C, Prieur F, Raad S, Rey JM, Ricou A, Salle L, Saule C, Sevenet N, Simaga F, Sobol H, Suybeng V, Tennevet I, Tenreiro H, Tinat J, Toulas C, Turbiez I, Uhrhammer N, Vande Perre P, Vaur D, Venat L, Viellard N, Villy MC, Warcoin M, Yvard A, Zattara H, Caron O, Lasset C, Remenieras A, Boutry-Kryza N, Castera L, Stoppa-Lyonnet D. Classification of 101 BRCA1 and BRCA2 variants of uncertain significance by cosegregation study: A powerful approach. Am J Hum Genet. 2021 Oct 7;108(10):1907-1923. doi: 10.1016/j.ajhg.2021.09.003. Epub 2021 Sep 30.

  PMID: 34597585 BACKGROUND

• Caputo SM, Telly D, Briaux A, Sesen J, Ceppi M, Bonnet F, Bourdon V, Coulet F, Castera L, Delnatte C, Hardouin A, Mazoyer S, Schultz I, Sevenet N, Uhrhammer N, Bonnet C, Tilkin-Mariame AF, Houdayer C, Moncoutier V, Andrieu C, French Covar Group Collaborators, Bieche I, Stern MH, Stoppa-Lyonnet D, Lidereau R, Toulas C, Rouleau E. 5' Region Large Genomic Rearrangements in the BRCA1 Gene in French Families: Identification of a Tandem Triplication and Nine Distinct Deletions with Five Recurrent Breakpoints. Cancers (Basel). 2021 Jun 25;13(13):3171. doi: 10.3390/cancers13133171.

  PMID: 34202044 BACKGROUND

• Meulemans L, Mesman RLS, Caputo SM, Krieger S, Guillaud-Bataille M, Caux-Moncoutier V, Leone M, Boutry-Kryza N, Sokolowska J, Revillion F, Delnatte C, Tubeuf H, Soukarieh O, Bonnet-Dorion F, Guibert V, Bronner M, Bourdon V, Lizard S, Vilquin P, Privat M, Drouet A, Grout C, Calleja FMGR, Golmard L, Vrieling H, Stoppa-Lyonnet D, Houdayer C, Frebourg T, Vreeswijk MPG, Martins A, Gaildrat P. Skipping Nonsense to Maintain Function: The Paradigm of BRCA2 Exon 12. Cancer Res. 2020 Apr 1;80(7):1374-1386. doi: 10.1158/0008-5472.CAN-19-2491. Epub 2020 Feb 11.

  PMID: 32046981 BACKGROUND

• Tubeuf H, Caputo SM, Sullivan T, Rondeaux J, Krieger S, Caux-Moncoutier V, Hauchard J, Castelain G, Fievet A, Meulemans L, Revillion F, Leone M, Boutry-Kryza N, Delnatte C, Guillaud-Bataille M, Cleveland L, Reid S, Southon E, Soukarieh O, Drouet A, Di Giacomo D, Vezain M, Bonnet-Dorion F, Bourdon V, Larbre H, Muller D, Pujol P, Vaz F, Audebert-Bellanger S, Colas C, Venat-Bouvet L, Solano AR, Stoppa-Lyonnet D, Houdayer C, Frebourg T, Gaildrat P, Sharan SK, Martins A. Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by Using BRCA2 Exon 3 as a Model System. Cancer Res. 2020 Sep 1;80(17):3593-3605. doi: 10.1158/0008-5472.CAN-20-0895. Epub 2020 Jul 8.

  PMID: 32641407 BACKGROUND

• Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadalo L, Aalfs CM, Agata S, Aittomaki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmana J, Barbieri E, Bartram CR, Blanco A, Blumcke B, Bonache S, Bonanni B, Borg A, Bortesi B, Brunet J, Bruzzone C, Bucksch K, Cagnoli G, Caldes T, Caliebe A, Caligo MA, Calvello M, Capone GL, Caputo SM, Carnevali I, Carrasco E, Caux-Moncoutier V, Cavalli P, Cini G, Clarke EM, Concolino P, Cops EJ, Cortesi L, Couch FJ, Darder E, de la Hoya M, Dean M, Debatin I, Del Valle J, Delnatte C, Derive N, Diez O, Ditsch N, Domchek SM, Dutrannoy V, Eccles DM, Ehrencrona H, Enders U, Evans DG, Farra C, Faust U, Felbor U, Feroce I, Fine M, Foulkes WD, Galvao HCR, Gambino G, Gehrig A, Gensini F, Gerdes AM, Germani A, Giesecke J, Gismondi V, Gomez C, Gomez Garcia EB, Gonzalez S, Grau E, Grill S, Gross E, Guerrieri-Gonzaga A, Guillaud-Bataille M, Gutierrez-Enriquez S, Haaf T, Hackmann K, Hansen TVO, Harris M, Hauke J, Heinrich T, Hellebrand H, Herold KN, Honisch E, Horvath J, Houdayer C, Hubbel V, Iglesias S, Izquierdo A, James PA, Janssen LAM, Jeschke U, Kaulfuss S, Keupp K, Kiechle M, Kolbl A, Krieger S, Kruse TA, Kvist A, Lalloo F, Larsen M, Lattimore VL, Lautrup C, Ledig S, Leinert E, Lewis AL, Lim J, Loeffler M, Lopez-Fernandez A, Lucci-Cordisco E, Maass N, Manoukian S, Marabelli M, Matricardi L, Meindl A, Michelli RD, Moghadasi S, Moles-Fernandez A, Montagna M, Montalban G, Monteiro AN, Montes E, Mori L, Moserle L, Muller CR, Mundhenke C, Naldi N, Nathanson KL, Navarro M, Nevanlinna H, Nichols CB, Niederacher D, Nielsen HR, Ong KR, Pachter N, Palmero EI, Papi L, Pedersen IS, Peissel B, Perez-Segura P, Pfeifer K, Pineda M, Pohl-Rescigno E, Poplawski NK, Porfirio B, Quante AS, Ramser J, Reis RM, Revillion F, Rhiem K, Riboli B, Ritter J, Rivera D, Rofes P, Rump A, Salinas M, Sanchez de Abajo AM, Schmidt G, Schoenwiese U, Seggewiss J, Solanes A, Steinemann D, Stiller M, Stoppa-Lyonnet D, Sullivan KJ, Susman R, Sutter C, Tavtigian SV, Teo SH, Teule A, Thomassen M, Tibiletti MG, Tischkowitz M, Tognazzo S, Toland AE, Tornero E, Torngren T, Torres-Esquius S, Toss A, Trainer AH, Tucker KM, van Asperen CJ, van Mackelenbergh MT, Varesco L, Vargas-Parra G, Varon R, Vega A, Velasco A, Vesper AS, Viel A, Vreeswijk MPG, Wagner SA, Waha A, Walker LC, Walters RJ, Wang-Gohrke S, Weber BHF, Weichert W, Wieland K, Wiesmuller L, Witzel I, Wockel A, Woodward ER, Zachariae S, Zampiga V, Zeder-Goss C; KConFab Investigators; Lazaro C, De Nicolo A, Radice P, Engel C, Schmutzler RK, Goldgar DE, Spurdle AB. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019 Sep;40(9):1557-1578. doi: 10.1002/humu.23818.

  PMID: 31131967 BACKGROUND

• Caputo SM, Leone M, Damiola F, Ehlen A, Carreira A, Gaidrat P, Martins A, Brandao RD, Peixoto A, Vega A, Houdayer C, Delnatte C, Bronner M, Muller D, Castera L, Guillaud-Bataille M, Sokilde I, Uhrhammer N, Demontety S, Tubeuf H, Castelain G; French COVAR group collaborators; Jensen UB, Petitalot A, Krieger S, Lefol C, Moncoutier V, Boutry-Kryza N, Nielsen HR, Sinilnikova O, Stoppa-Lyonnet D, Spurdle AB, Teixeira MR, Coulet F, Thomassen M, Rouleau E. Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer. Oncotarget. 2018 Apr 3;9(25):17334-17348. doi: 10.18632/oncotarget.24671. eCollection 2018 Apr 3.

  PMID: 29707112 BACKGROUND

• Moghadasi S, Meeks HD, Vreeswijk MP, Janssen LA, Borg A, Ehrencrona H, Paulsson-Karlsson Y, Wappenschmidt B, Engel C, Gehrig A, Arnold N, Hansen TVO, Thomassen M, Jensen UB, Kruse TA, Ejlertsen B, Gerdes AM, Pedersen IS, Caputo SM, Couch F, Hallberg EJ, van den Ouweland AM, Collee MJ, Teugels E, Adank MA, van der Luijt RB, Mensenkamp AR, Oosterwijk JC, Blok MJ, Janin N, Claes KB, Tucker K, Viassolo V, Toland AE, Eccles DE, Devilee P, Van Asperen CJ, Spurdle AB, Goldgar DE, Garcia EG. The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium. J Med Genet. 2018 Jan;55(1):15-20. doi: 10.1136/jmedgenet-2017-104560. Epub 2017 May 10.

  PMID: 28490613 BACKGROUND

• Spurdle AB, Whiley PJ, Thompson B, Feng B, Healey S, Brown MA, Pettigrew C; kConFab; Van Asperen CJ, Ausems MG, Kattentidt-Mouravieva AA, van den Ouweland AM; Dutch Belgium UV Consortium; Lindblom A, Pigg MH, Schmutzler RK, Engel C, Meindl A; German Consortium of Hereditary Breast and Ovarian Cancer; Caputo S, Sinilnikova OM, Lidereau R; French COVAR group collaborators; Couch FJ, Guidugli L, Hansen Tv, Thomassen M, Eccles DM, Tucker K, Benitez J, Domchek SM, Toland AE, Van Rensburg EJ, Wappenschmidt B, Borg A, Vreeswijk MP, Goldgar DE; ENIGMA Consortium. BRCA1 R1699Q variant displaying ambiguous functional abrogation confers intermediate breast and ovarian cancer risk. J Med Genet. 2012 Aug;49(8):525-32. doi: 10.1136/jmedgenet-2012-101037.

  PMID: 22889855 BACKGROUND

MeSH Terms

Conditions

Genetic Predisposition to Disease

Condition Hierarchy (Ancestors)

Disease Susceptibility; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Chrystelle COLAS, MD, PhD

  Institut Curie

  STUDY CHAIR

• Sandrine CAPUTO, PhD

  Institut Curie

  STUDY DIRECTOR

Central Study Contacts

Sandrine CAPUTO, PhD

CONTACT

33172389367; sandrine.caputo@curie.fr

Isabelle TURBIEZ, Project Manager

CONTACT

33147111659; isabelle.turbiez@curie.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2012
• First Posted: September 21, 2012
• Study Start: July 2, 2012
• Primary Completion (Estimated): July 2, 2037
• Study Completion (Estimated): January 2, 2038
• Last Updated: May 27, 2026

Record last verified: 2026-05

Locations

FR (58); MA (1); NE (1); RE (1); GU (1)