COsegregation of VARiants in Panel of Genes (COVAR)

May 22, 2026 updated by: Institut Curie

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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).

Study Type

Interventional

Enrollment (Estimated)

11000

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Amiens, France, 80054
        • Recruiting
        • CHU Amiens - Hôpital Nord
        • Contact:
          • Gilles MORIN, MD
        • Principal Investigator:
          • Gilles MORIN, MD
      • Angers, France, 49933
        • Recruiting
        • ICO - Centre Paul Papin
        • Contact:
          • Marie COUDERT, MD
        • Principal Investigator:
          • Marie COUDERT, MD
      • Angoulême, France, 16959
        • Recruiting
        • Centre Hospitalier d'Angoulème
        • Contact:
          • Stéphanie CHIEZE-VALERO, MD
        • Principal Investigator:
          • Stéphanie CHIEZE-VALERO, MD
      • Avignon, France, 84918
        • Recruiting
        • Institut Sainte-Catherine
        • Contact:
          • Hélène DREYFUS, MD
        • Principal Investigator:
          • Hélène DREYFUS, MD
      • Besançon, France, 25030
        • Recruiting
        • Chu Besancon
        • Contact:
          • Marie-Agnès COLLONGE-RAME, MD
        • Principal Investigator:
          • Marie-Agnès COLLONGE-RAME, MD
      • Bordeaux, France, 33076
        • Recruiting
        • Institut Bergonie
        • Contact:
          • Virginie BUBIEN, MD
        • Principal Investigator:
          • Virginie BUBIEN, MD
      • Bordeaux, France, 33076
        • Recruiting
        • Groupe Hospitalier Pellegrin
        • Contact:
          • Julie TINAT, MD
        • Principal Investigator:
          • Julie TINAT, MD
      • Bourges, France, 18020
        • Recruiting
        • Centre Hospitalier Jacques Coeur
        • Principal Investigator:
          • Isabelle MORTEMOUSQUE, MD
        • Contact:
          • Isabelle MORTEMOUSQUE, MD
      • Brest, France, 29200
        • Recruiting
        • CHU Morvan de Brest
        • Contact:
          • Marc PLANES, MD
        • Principal Investigator:
          • Marc PLANES, MD
      • Caen, France, 14076
        • Recruiting
        • Centre Francois Baclesse
        • Contact:
          • Pascaline BERTHET, MD
        • Principal Investigator:
          • Pascaline BERTHET, MD
      • Chambéry, France, 73011
        • Recruiting
        • Centre Hospitalier Hôtel Dieu
        • Contact:
          • Sandra FERRER, MD
        • Principal Investigator:
          • Sandra FERRER, MD
      • Clermont-Ferrand, France, 63011
        • Recruiting
        • Centre Jean Perrin
        • Contact:
          • Mathilde GAY-BELLILE, MD
        • Principal Investigator:
          • Mathilde GAY-BELLILE, MD
      • Colmar, France, 68024
        • Not yet recruiting
        • Hôpital Civil de Colmar
        • Contact:
          • Jean-Marc LIMACHER
        • Principal Investigator:
          • Jean-Marc LIMACHER, MD
      • Dijon, France, 21079
        • Recruiting
        • CHU de DIJON
        • Contact:
          • Laurence FAIVRE-OLIVIER, MD
        • Principal Investigator:
          • Laurence FAIVRE-OLIVIER, MD
      • Grenoble, France, 38043
        • Recruiting
        • CHU de Grenoble
        • Contact:
          • Clémentine LEGRAND, MD
        • Principal Investigator:
          • Clémentine LEGRAND, MD
      • La Roche-sur-Yon, France, 85925
        • Not yet recruiting
        • CHD Vendee
        • Contact:
          • Céline BIHAN, MD
        • Principal Investigator:
          • Céline BIHAN, MD
      • La Rochelle, France, 17019
        • Recruiting
        • Groupe Hospitalier La Rochelle-Ré-Aunis
        • Contact:
          • Stéphanie CHIEZE-VALERO, MD
        • Principal Investigator:
          • Stéphanie CHIEZE-VALERO, MD
      • Le Havre, France, 76083
        • Recruiting
        • Hôpital Flaubert
        • Contact:
          • Elodie LACAZE, MD
        • Principal Investigator:
          • Elodie LACAZE, MD
      • Lille, France, 59000
        • Recruiting
        • Centre Oscar Lambret
        • Contact:
          • Audrey MAILLIEZ, MD
        • Principal Investigator:
          • Audrey MAILLIEZ, MD
      • Lille, France, 59037
        • Recruiting
        • CHRU Lille
        • Contact:
          • Sophie LEJEUNE, MD
        • Principal Investigator:
          • Sophie LEJEUNE, MD
      • Limoges, France, 87042
        • Recruiting
        • CHU Dupuytren
        • Contact:
          • Laurence VENAT-BOUVET, MD
        • Principal Investigator:
          • Laurence VENAT-BOUVET, MD
      • Lyon, France, 69373
        • Recruiting
        • Centre Leon Berard
        • Contact:
          • Christine LASSET, MD
        • Principal Investigator:
          • Christine LASSET, MD
      • Lyon, France, 69229
        • Recruiting
        • Hospices Civils de Lyon
        • Contact:
          • Stéphane PINSON, MD
        • Principal Investigator:
          • Stéphane PINSON, MD
      • Marseille, France, 13009
        • Recruiting
        • Institut Paoli Calmettes
        • Contact:
          • Hagay SOBOL, PhD
        • Principal Investigator:
          • Hagay SOBOL, PhD
      • Marseille, France, 13385
        • Recruiting
        • CHU La Timone
        • Contact:
          • Hélène ZATTARA, MD
        • Principal Investigator:
          • Hélène ZATTARA, MD
      • Montpellier, France, 34295
        • Recruiting
        • CHU Arnaud de Villeneuve
        • Contact:
          • Isabelle COUPIER, MD
        • Principal Investigator:
          • Isabelle COUPIER, MD
      • Nantes, France, 44202
        • Recruiting
        • Centre Catherine de Sienne
        • Contact:
          • Cyriac BLONZ, MD
        • Principal Investigator:
          • Cyriac BLONZ, MD
      • Nice, France, 06189
        • Recruiting
        • Centre Antoine Lacassagne
        • Contact:
          • Véronique MARI, MD
        • Principal Investigator:
          • Véronique MARI, MD
      • Niort, France, 79021
        • Recruiting
        • Centre Hospitalier Georges Renon
        • Contact:
          • Stéphanie CHIEZE-VALERO, MD
        • Principal Investigator:
          • Stéphanie CHIEZE-VALERO, MD
      • Nîmes, France, 30029
        • Recruiting
        • CHRU Caremeau
        • Contact:
          • Jean CHIESA, MD
        • Principal Investigator:
          • Jean CHIESA, MD
      • Orléans, France, 45067
        • Recruiting
        • Hôpital de la Source
        • Contact:
          • Edouard COTTEREAU, MD
        • Principal Investigator:
          • Edouard COTTEREAU, MD
      • Paris, France, 75012
        • Recruiting
        • Hopital Saint-Antoine
        • Contact:
          • Antoine DARDENNE, MD
        • Principal Investigator:
          • Antoine DARDENNE, MD
      • Paris, France, 75475
        • Recruiting
        • Hôpital Saint-Louis
        • Contact:
          • Odile COHEN-HAGUENAUER, MD
        • Principal Investigator:
          • Odile COHEN-HAGUENAUER, MD
      • Paris, France, 75013
        • Recruiting
        • Groupe Hospitalier Pitie-Salpetriere
        • Contact:
          • Véronica CUSIN, MD
        • Principal Investigator:
          • Véronica CUSIN, MD
      • Paris, France, 75020
        • Recruiting
        • Hopital Tenon
        • Contact:
          • Clémence EVREVIN, MD
        • Principal Investigator:
          • Clémence EVREVIN, MD
      • Paris, France, 75908
        • Recruiting
        • HEGP
        • Contact:
          • Pierre-Laurent PUIG, Phd
        • Principal Investigator:
          • Pierre-Laurent PUIG, Phd
      • Poissy, France, 78303
        • Not yet recruiting
        • Centre Hospitalier Intercommunal Poissy -Saint Germain-en-Laye
        • Principal Investigator:
          • Claudia RIZZO, MD
        • Contact:
          • Claudia RIZZO, MD
      • Poitiers, France, 86021
        • Recruiting
        • Chu La Miletrie
        • Principal Investigator:
          • David TOUGERON, MD
        • Contact:
          • David TOUGERON, MD
      • Reims, France, 51092
        • Recruiting
        • CHU de Reims
        • Contact:
          • Hugo THORN, MD
        • Principal Investigator:
          • Hugo THORN, MD
      • Reims, France, 51100
        • Recruiting
        • Institut Jean Godinot
        • Principal Investigator:
          • Aude-Marie SAVOYE, MD
        • Contact:
          • Aude-Marie SAVOYE, MD
      • Reims, France, 51100
        • Recruiting
        • ICC Courlancy
        • Contact:
          • Fanny BRAYOTEL, MD
        • Principal Investigator:
          • Fanny BRAYOTEL, MD
      • Rennes, France, 35042
        • Recruiting
        • Centre Eugène Marquis
        • Contact:
          • Louise CRIVELLI, MD
        • Principal Investigator:
          • Louise CRIVELLI, MD
      • Rennes, France, 35203
        • Not yet recruiting
        • CHU Rennes - Hôpital Sud
        • Contact:
          • Philippe DENIZEAU, MD
        • Principal Investigator:
          • Philippe DENIZEAU, MD
      • Rouen, France, 76031
        • Recruiting
        • CHU de ROUEN
        • Contact:
          • Isabelle TENNEVET, MD
        • Principal Investigator:
          • Isabelle TENNEVET, MD
      • Saint-Etienne, France, 42055
        • Recruiting
        • CHU Saint Etienne
        • Contact:
          • Fabienne PRIEUR, MD
        • Principal Investigator:
          • Fabienne PRIEUR, MD
      • Saint-Herblain, France, 44804
        • Recruiting
        • ICO - Centre René Gauducheau
        • Contact:
          • Capucine DELNATTE, MD
        • Principal Investigator:
          • Capucine DELNATTE, MD
      • Strasbourg, France, 67200
        • Recruiting
        • Hopital de Hautepierre - Hôpital Universitaire
        • Contact:
          • Morgane BOEDEC, MD
        • Principal Investigator:
          • Morgane BOEDEC, MD
      • Strasbourg, France, 67033
        • Recruiting
        • CLCC Paul Strauss
        • Contact:
          • Manon CHRETIEN, MD
        • Principal Investigator:
          • Manon CHRETIEN, MD
      • Toulouse, France, 31059
        • Recruiting
        • Institut Claudius Regaud - IUCT - Oncopole
        • Principal Investigator:
          • Laurence Gladieff, MD
        • Contact:
          • Laurence GLADIEFF, MD
      • Tours, France, 37044
        • Recruiting
        • CHU Bretonneau
        • Principal Investigator:
          • Isabelle MORTEMOUSQUE, MD
        • Contact:
          • Isabelle MORTEMOUSQUE, MD
      • Troyes, France, 10003
        • Recruiting
        • CH Simone VEIL
        • Contact:
          • Charlotte CAILLE-BENIGNI, MD
        • Principal Investigator:
          • Charlotte CAILLE-BENIGNI, MD
      • Valence, France, 26953
        • Recruiting
        • Centre Hospitalier de Valence
        • Contact:
          • Marie-Noëlle BONNET-DUPEYRON, MD
        • Principal Investigator:
          • Marie-Noëlle BONNET-DUPEYRON, MD
      • Vandœuvre-lès-Nancy, France, 54511
        • Withdrawn
        • Centre Alexis Vautrin
      • Vandœuvre-lès-Nancy, France, 54511
        • Recruiting
        • CHU Nancy - Hôpital Brabois
        • Contact:
          • Jean-Marie RAVEL, MD
        • Principal Investigator:
          • Jean-Marie RAVEL, MD
      • Villejuif, France, 94805
        • Recruiting
        • Gustave Roussy
        • Contact:
          • Olivier CARON, MD
        • Principal Investigator:
          • Olivier CARON, MD
    • Corsica
      • Bastia, Corsica, France, 20604
        • Not yet recruiting
        • Centre Hospitalier de Bastia
        • Contact:
          • Franck LE DUFF, MD
        • Principal Investigator:
          • LE DUFF Franck, MD
    • Haut de Seine
      • Saint-Cloud, Haut de Seine, France, 92210
        • Recruiting
        • Institut Curie - Saint-Cloud site
        • Contact:
        • Principal Investigator:
          • Emmanuelle FOURME, MD
    • Île-de-France Region
      • Paris, Île-de-France Region, France, 75005
        • Recruiting
        • Institut Curie - Paris site
        • Contact:
        • Principal Investigator:
          • Chrystelle COLAS, MD, PhD
  • Guadeloupe
      • Pointe-à-Pitre, Guadeloupe, 97110
        • Recruiting
        • CHU de Pointe à Pitre
        • Contact:
          • Marilyn LACKMY-PORT-LIS, MD
        • Principal Investigator:
          • Marilyn LACKMY-PORT-LIS, MD
  • Martinique
      • Fort-de-France, Martinique, 97261
        • Recruiting
        • CHU de Fort de France
        • Contact:
          • Odile BERA, MD
        • Principal Investigator:
          • Odile BERA, MD
  • New Caledonia
      • Noumea, New Caledonia, 98849
        • Not yet recruiting
        • Centre Hospitalier Territorial Gaston Bourret
        • Contact:
          • Catherine CHARLIER, MD
        • Principal Investigator:
          • Catherine CHARLIER, MD
  • Reunion
      • Saint-Pierre, Reunion, 97410
        • Recruiting
        • CHU Sud Réunion Saint-Pierre
        • Contact:
          • Hanitra RANJATOELINA, MD
        • Principal Investigator:
          • Hanitra RANJATOELINA, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

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"

Exclusion Criteria:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Covar
Genetic: salivary kit
The saliva samples will be made of selected related (DNA).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Perform the co-segregation analysis of the selected VUS (class 3) or likely pathogenic variant (class 4) in the families.
Time Frame: up to 15 years
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Propose a standardized method to classify as many variants as possible from the national of the Genetics and Cancer Group (GGC) of Unicancer.
Time Frame: up to 15 years
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.
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.
Time Frame: up to 15 years
Number of VUS (class 3) or likely pathogene (class 4) classified 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.
Time Frame: up to 15 years
Number of new hypomorphic variants and determination of their penetrance.
up to 15 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Institut Curie

Investigators

  • Study Director: Sandrine CAPUTO, PhD, Institut Curie
  • Study Chair: Chrystelle COLAS, MD, PhD, Institut Curie

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 2, 2012

Primary Completion (Estimated)

July 2, 2037

Study Completion (Estimated)

January 2, 2038

Study Registration Dates

First Submitted

May 14, 2012

First Submitted That Met QC Criteria

September 20, 2012

First Posted (Estimated)

September 21, 2012

Study Record Updates

Last Update Posted (Actual)

May 27, 2026

Last Update Submitted That Met QC Criteria

May 22, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IC 2011-11

Plan for Individual participant data (IPD)

Study Data/Documents

  1. Database
    Information identifier: FrOG program
    Information comments: The FrOG program aims to organize the collection of all genetic variants associated with cancer

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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