Gene Mutation-Related CancerCOVARNCT01689584
COsegregation of VARiants in Panel of Genes
A study testing salivary kit in people with Gene Mutation-Related Cancer and Genetic Predisposition, run by Institut Curie at 62 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gene Mutation-Related Cancer, Genetic Predisposition
- What is being tested?
- salivary kit
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 11,000 participants
- Where
- 62 sitesin 5 countries
- Study dates
- 2 Jul 2012to 2 Jan 2038
- Phase
- Interventional
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 10Show fewer
- 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"
Who cannot join
- Minors
- Persons deprived of liberty or under guardianship (including curators).
- Absence of signed written inform consent
Trial locations and contacts
62 sites in 5 countries. Contact the study team or a site near you to ask about taking part.
62 sites in 5 countries
France58 sites, 57 recruiting
- Recruiting
CHU Amiens - Hôpital Nord
Amiens, 80054
Gilles MORIN, MD
Gilles MORIN, MD
- Recruiting
ICO - Centre Paul Papin
Angers, 49933
Marie COUDERT, MD
Marie COUDERT, MD
- Recruiting
Centre Hospitalier d'Angoulème
Angoulême, 16959
Stéphanie CHIEZE-VALERO, MD
Stéphanie CHIEZE-VALERO, MD
- Recruiting
Institut Sainte-Catherine
Avignon, 84918
Hélène DREYFUS, MD
Hélène DREYFUS, MD
- Not yet recruiting
Centre Hospitalier de Bastia
Bastia, Corsica, 20604
Franck LE DUFF, MD
LE DUFF Franck, MD
- Recruiting
CHU Besançon
Besançon, 25030
Marie-Agnès COLLONGE-RAME, MD
Marie-Agnès COLLONGE-RAME, MD
- Recruiting
Groupe Hospitalier Pellegrin
Bordeaux, 33076
Julie TINAT, MD
Julie TINAT, MD
- Recruiting
Institut Bergonié
Bordeaux, 33076
Virginie BUBIEN, MD
Virginie BUBIEN, MD
- Recruiting
Centre Hospitalier Jacques Coeur
Bourges, 18020
Isabelle MORTEMOUSQUE, MD
Isabelle MORTEMOUSQUE, MD
- Recruiting
CHU Morvan de Brest
Brest, 29200
Marc PLANES, MD
Marc PLANES, MD
- Recruiting
Centre François Baclesse
Caen, 14076
Pascaline BERTHET, MD
Pascaline BERTHET, MD
- Recruiting
Centre Hospitalier Hôtel Dieu
Chambéry, 73011
Sandra FERRER, MD
Sandra FERRER, MD
- Recruiting
Centre Jean Perrin
Clermont-Ferrand, 63011
Mathilde GAY-BELLILE, MD
Mathilde GAY-BELLILE, MD
- Not yet recruiting
Hôpital Civil de Colmar
Colmar, 68024
Jean-Marc LIMACHER
Jean-Marc LIMACHER, MD
- Recruiting
CHU de Dijon
Dijon, 21079
Sophie NAMBOT, MD, 33 4 77 82 81 16, sophie.nambot@chu-dijon.fr
Laurence FAIVRE-OLIVIER, MD
- Recruiting
CHU de Grenoble
Grenoble, 38043
Clémentine LEGRAND, MD
Clémentine LEGRAND, MD
- Not yet recruiting
CHD Vendée
La Roche-sur-Yon, 85925
Céline BIHAN, MD
Céline BIHAN, MD
- Recruiting
Groupe Hospitalier La Rochelle-Ré-Aunis
La Rochelle, 17019
Stéphanie CHIEZE-VALERO, MD
Stéphanie CHIEZE-VALERO, MD
- Recruiting
Hôpital Flaubert
Le Havre, 76083
Elodie LACAZE, MD
Elodie LACAZE, MD
- Recruiting
Centre Oscar Lambret
Lille, 59000
Audrey MAILLIEZ, MD
Audrey MAILLIEZ, MD
- Recruiting
Chru Lille
Lille, 59037
Sophie LEJEUNE, MD
Sophie LEJEUNE, MD
- Recruiting
CHU Dupuytren
Limoges, 87042
Laurence VENAT-BOUVET, MD
Laurence VENAT-BOUVET, MD
- Recruiting
Hospices Civils de Lyon
Lyon, 69229
Stéphane PINSON, MD
Stéphane PINSON, MD
- Recruiting
Centre Léon Bérard
Lyon, 69373
Christine LASSET, MD
Christine LASSET, MD
- Recruiting
Institut Paoli Calmettes
Marseille, 13009
Hagay SOBOL, PhD
Hagay SOBOL, PhD
- Recruiting
CHU La Timone
Marseille, 13385
Hélène ZATTARA, MD
Hélène ZATTARA, MD
- Recruiting
CHU Arnaud de Villeneuve
Montpellier, 34295
Isabelle COUPIER, MD
Isabelle COUPIER, MD
- Recruiting
Centre Catherine de Sienne
Nantes, 44202
Cyriac BLONZ, MD
Cyriac BLONZ, MD
- Recruiting
Centre Antoine Lacassagne
Nice, 06189
Véronique MARI, MD
Véronique MARI, MD
- Recruiting
CHRU Caremeau
Nîmes, 30029
Jean CHIESA, MD
Jean CHIESA, MD
- Recruiting
Centre Hospitalier Georges Renon
Niort, 79021
Stéphanie CHIEZE-VALERO, MD
Stéphanie CHIEZE-VALERO, MD
- Recruiting
Hôpital de la Source
Orléans, 45067
Edouard COTTEREAU, MD
Edouard COTTEREAU, MD
- Recruiting
Hôpital Saint-Antoine
Paris, 75012
Antoine DARDENNE, MD
Antoine DARDENNE, MD
- Recruiting
Groupe Hospitalier Pitié-Salpêtrière
Paris, 75013
Véronica CUSIN, MD
Véronica CUSIN, MD
- Recruiting
Hôpital Tenon
Paris, 75020
Clémence EVREVIN, MD
Clémence EVREVIN, MD
- Recruiting
Hôpital Saint-Louis
Paris, 75475
Odile COHEN-HAGUENAUER, MD
Odile COHEN-HAGUENAUER, MD
- Recruiting
HEGP
Paris, 75908
Pierre-Laurent PUIG, Phd
Pierre-Laurent PUIG, Phd
- Recruiting
Institut Curie - Paris site
Paris, Île-de-France Region, 75005
Sandrine CAPUTO, PhD, sandrine.caputo@curie.fr
Chrystelle COLAS, MD, PhD
- Not yet recruiting
Centre Hospitalier Intercommunal Poissy -Saint Germain-en-Laye
Poissy, 78303
Claudia RIZZO, MD
Claudia RIZZO, MD
- Recruiting
CHU La Milétrie
Poitiers, 86021
David TOUGERON, MD
David TOUGERON, MD
- Recruiting
CHU de Reims
Reims, 51092
Hugo THORN, MD
Hugo THORN, MD
- Recruiting
ICC Courlancy
Reims, 51100
Fanny BRAYOTEL, MD
Fanny BRAYOTEL, MD
- Recruiting
Institut Jean Godinot
Reims, 51100
Aude-Marie SAVOYE, MD
Aude-Marie SAVOYE, MD
- Recruiting
Centre Eugène Marquis
Rennes, 35042
Louise CRIVELLI, MD
Louise CRIVELLI, MD
- Not yet recruiting
CHU Rennes - Hôpital Sud
Rennes, 35203
Philippe DENIZEAU, MD
Philippe DENIZEAU, MD
- Recruiting
CHU de Rouen
Rouen, 76031
Isabelle TENNEVET, MD
Isabelle TENNEVET, MD
- Recruiting
Institut Curie - Saint-Cloud site
Saint-Cloud, Haut de Seine, 92210
Emmanuelle FOURME, PhD, emmanuelle.fourme@curie.fr
Emmanuelle FOURME, MD
- Recruiting
CHU Saint Etienne
Saint-Etienne, 42055
Marine LEBRUN, MD, 33 4 77 82 81 16, marine.lebrun@chu-st-etienne.fr
Fabienne PRIEUR, MD
- Recruiting
ICO - Centre René Gauducheau
Saint-Herblain, 44804
Capucine DELNATTE, MD
Capucine DELNATTE, MD
- Recruiting
CLCC Paul Strauss
Strasbourg, 67033
Manon CHRETIEN, MD
Manon CHRETIEN, MD
- Recruiting
Hopital de Hautepierre - Hôpital Universitaire
Strasbourg, 67200
Morgane BOEDEC, MD
Morgane BOEDEC, MD
- Recruiting
Institut Claudius Regaud - IUCT - Oncopole
Toulouse, 31059
Laurence GLADIEFF, MD
Laurence GLADIEFF, MD
- Recruiting
CHU Bretonneau
Tours, 37044
Isabelle MORTEMOUSQUE, MD
Isabelle MORTEMOUSQUE, MD
- Recruiting
CH Simone VEIL
Troyes, 10003
Charlotte CAILLE-BENIGNI, MD
Charlotte CAILLE-BENIGNI, MD
- Recruiting
Centre Hospitalier de Valence
Valence, 26953
Marie-Noëlle BONNET-DUPEYRON, MD
Marie-Noëlle BONNET-DUPEYRON, MD
- Withdrawn
Centre Alexis Vautrin
Vandœuvre-lès-Nancy, 54511
- Recruiting
CHU Nancy - Hôpital Brabois
Vandœuvre-lès-Nancy, 54511
Jean-Marie RAVEL, MD
Jean-Marie RAVEL, MD
- Recruiting
Gustave Roussy
Villejuif, 94805
Olivier CARON, MD
Olivier CARON, MD
Guadeloupe1 site, 1 recruiting
- Recruiting
CHU de Pointe à Pitre
Pointe-à-Pitre, 97110
Marilyn LACKMY-PORT-LIS, MD
Marilyn LACKMY-PORT-LIS, MD
Martinique1 site, 1 recruiting
- Recruiting
CHU de Fort de France
Fort-de-France, 97261
Odile BERA, MD
Odile BERA, MD
New Caledonia1 site, 1 recruiting
- Not yet recruiting
Centre Hospitalier Territorial Gaston Bourret
Noumea, 98849
Catherine CHARLIER, MD
Catherine CHARLIER, MD
Reunion1 site, 1 recruiting
- Recruiting
CHU Sud Réunion Saint-Pierre
Saint-Pierre, 97410
Hanitra RANJATOELINA, MD
Hanitra RANJATOELINA, MD
About this study
Official title: Study of Family COsegregation of Nucleotide VARiants in the Panel of Genes to Validate Their Use in Genetic Counseling
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.
Read the detailed description
Originally, the COVAR study was designed to investigate Variants of Unknown biological Significance (VUS) in BRCA1 (BReast Cancer 1) and BRCA2 (BReast Cancer 2) genes, which are the two major genes identified in hereditary breast and/or ovarian cancers. Over time, it has evolved alongside advances in genetic diagnostics. First, it incorporated the Partner and Localizer of BRCA2 (PALB2) gene, included in routine testing since 2015, and more recently it has expanded to include all genes analyzed in multigene panels for families suspected of hereditary cancer predisposition syndromes.
To support variant interpretation, national databases have been developed. The Universal Mutation DataBase BRCA1/BRCA2 (UMD-BRCA1/BRCA2), maintained within the French oncogenetics network, collects anonymized genetic data and enables the identification of families sharing the same variants. More recently, the FrOG database (established in 2020) has expanded this approach to 38 genes and over 66,000 families, compiling nearly 20,000 distinct variants, including thousands of VUS and likely pathogenic variants.
As knowledge has progressed, classification systems have evolved. The term VUS now strictly refers to class 3 variants, while class 4 (likely pathogenic) variants are increasingly actionable in clinical care under certain conditions. Additionally, a subset of class 5 variants with intermediate effects ("hypomorphic" variants) has been recognized, highlighting variability in risk depending on the type of genetic alteration. These variants are now included in COVAR to refine risk estimates.
One of the key measurable parameters for classification of variants of interest is their co-segregation with the disease. The average size of French families is relatively small, the information of variant co-segregation limited to one family would not be significant. However, the compilation of co-segregation results obtained from several families will allow to obtain more precise and complete estimations of the pathogenicity of a given variant. The main objective of the COVAR study (COsegregation VARiants) is to organize such co-segregation studies using national database data, in order to determine the pathogenicity of selected variants and improve genetic counseling.
In the selected families the index case will invite the family members (affected and unaffected) to provide a sample of salivary fluid to test the presence of the VUS (class 3). The probability that a VUS is causal will be calculated from the cosegregation data using a Bayesian model. The results will be integrated in the multifactorial model described by D. Goldgar, model integrating different parameters.
For class 4 and hypomorphic class 5 variants, relatives are advised to attend oncogenetic consultations for targeted diagnostic testing without additional sampling. Genetic analyses for class 3 variants are conducted by the identifying laboratory, while classes 4-5 analyses are performed by affiliated GGC laboratories.
Results are sent anonymously to the coordinating center for statistical analysis, and only overall variant classification (not individual results) is communicated back.
If a variant is found pathogenic, the index case is informed, enabling family communication, possible presymptomatic testing (class 3), and potential clinical management impact (classes 4-5).
- Being tested
- salivary kit
- Keywords
- BRCA1, BRCA2, VUS, co-segregation, genetic counseling, PALB2, panel of genes, variant, hypomorphic, Hereditary cancer (breast, ovarian, prostate, pancreas, digestive track)
- Medical subject headings
- Genetic Predisposition to Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
salivary kitGenetic
The saliva samples will be made of selected related (DNA).
| Study group | Role | What they receive |
|---|---|---|
| Covar | Other | Not described Receives: Genetic: salivary kit |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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.
Provision of variant classifications to laboratories by the expert group based on the national FrOG database, along with harmonization of the conclusions regarding these variants.
Measured: 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.
Number of VUS (class 3) or likely pathogene (class 4) classified to guide genetic counselling
Measured: up to 15 years
Assess the penetrance of selected variants of interest, particularly hypomorphic pathogenic variant (hypomorphic class 5) shared across multiple families.
Number of new hypomorphic variants and determination of their penetrance.
Measured: up to 15 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2012 (estimated)
- Study start2 Jul 2012
- Primary completion2 Jul 2037 (estimated)
- Study completion2 Jan 2038 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Gene Mutation-Related CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 11,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Institut Curie
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Chrystelle COLAS, MD, PhD, Study chair, Institut CurieSandrine CAPUTO, PhD, Study director, Institut Curie
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01689584
- Sponsor's protocol ID
- IC 2011-11
- Acronym
- COVAR
- Status last verified
- Aug 2026
- First submitted
- 14 May 2012
- Last updated
- 1 Sep 2026
- Results posted
- No
- Data monitoring committee
- No
Publications
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.
PubMed 34597585Caputo 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.
PubMed 34202044Meulemans 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.
PubMed 32046981Tubeuf 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.
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