COsegregation of VARiants in Panel of Genes (COVAR)

January 16, 2024 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 classify reliably a maximum of VUS of the French database 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 explore 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. Since then the study has evolved, in parallel with the evolution of diagnosis, first introducing the PALB2 (Partner and localizer of BRCA2) gene explored in diagnosis since 2015 and now opening the study to all the genes of the panels performed in diagnosis in families with a genetic predisposition syndrome to cancers.

The French UMD (Universal Mutation Database)-BRCA1/2, accredited by the French National Cancer Institute, collects anonymous results of genetic tests performed by authorized French laboratories since 1995, giving a real-time vision of families carrying the same VUS. In september 2011, the French UMD-BRCA1/2 database comprised 706 different variants in 1,300 BRCA1 families and 1,089 different variants in 2,101 BRCA2 families. In April 2021, this database contained 1,651 different VSU for BRCA1, 3,015 different VUS for BRCA2, 471 different VUS for PALB2, 68 for RAD51C and 66 for RAD51D.

Since 2017, new genes have been explored in the diagnostic setting as they have been reported as predisposing factors for cancers. This list is constantly evolving (Moretta et al., 2018; Dhooge et al., 2020). Data collection for these genes is ongoing and a new database (FrOG) gathering all VUS and mutations identified in the French oncogenetic network has been set up. We have set up a consortium agreement at the end of 2020. This database gathers to date 12 genes and 11,912 different variants in more than 40,000 French families.

One of the key measurable parameters for classification of VUS as causal mutations 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 probability of causality of a given variant.

The objective of the COVAR study (COsegregation VARiants) is to organize co-segregation studies of the VUS of the database UMD-BRCA1/2, in order to determine the causal or non-causal nature of these variants. To organize the variants by their clinical relevance, a grid with 5 classes has been used: 1=neutral, 2=likely neutral, 3=VUS, 4=likely causal, 5=causal. The VUS of classes 3 and 4 will be candidates to co-segregation studies because they cannot be used for the 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. 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 as amino acid conservation, structural impact of the variant, co-occurrence with a pathogenic mutation, family history and tumor characteristics.

Study Type

Interventional

Enrollment (Estimated)

3500

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 - Hopital 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
      • Besancon, France, 25030
        • Recruiting
        • CHU Besançon
        • 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
      • Chambery, 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 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 Léon Bérard
        • Contact:
          • Christine LASSET, MD
        • Principal Investigator:
          • Christine LASSET, MD
      • Lyon, France, 69229
        • Recruiting
        • Hospices Civils de Lyon
        • Contact:
          • Sophie GIRAUD, MD
        • Principal Investigator:
          • Sophie GIRAUD, 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
        • Principal Investigator:
          • Alain Lortholary, MD
        • Contact:
          • Alain LORTHOLARY, 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:
          • E COTTEREAU, MD
        • Principal Investigator:
          • E COTTEREAU, MD
      • Paris, France, 75012
        • Recruiting
        • Hopital Saint-Antoine
        • Contact:
          • Antoine DARDENNE, MD
        • Principal Investigator:
          • Antoine DARDENNE, MD
      • Paris, France, 75475
        • Recruiting
        • Hopital 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
      • Poitiers, France, 86021
        • Recruiting
        • CHU la Milétrie
        • Contact:
          • Stéphanie CHIEZE-VALERO, MD
        • Principal Investigator:
          • Stéphanie CHIEZE-VALERO, MD
      • Reims, France, 51092
        • Recruiting
        • CHU de Reims
        • Contact:
          • Anne DURLACH, MD
        • Principal Investigator:
          • Anne DURLACH, MD
      • Reims, France, 51100
        • Recruiting
        • Institut Jean Godinot
        • Contact:
          • Tan Dat NGUYEN, PHD
        • Principal Investigator:
          • Tan Dat NGUYEN, PHD
      • 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
      • Rouen, France, 76031
        • Recruiting
        • CHU de Rouen
        • Contact:
          • Isabelle TENNEVET, MD
        • Principal Investigator:
          • Isabelle TENNEVET, MD
      • Saint-Herblain, France, 44804
        • Recruiting
        • ICO - Centre René Gauducheau
        • Contact:
          • Capucine DELNATTE, MD
        • Principal Investigator:
          • Capucine DELNATTE, MD
      • Saint-Étienne, France, 42055
        • Recruiting
        • Chu Saint Etienne
        • Contact:
          • Fabienne PRIEUR, MD
        • Principal Investigator:
          • Fabienne PRIEUR, MD
      • Strasbourg, France, 67033
        • Recruiting
        • Institut de Cancerologie Strasbourg Europe ICANS
        • Contact:
          • Philippe BOUDIER, MD
        • Principal Investigator:
          • Philippe BOUDIER, MD
      • Strasbourg, France, 67200
        • Recruiting
        • Hopital de Hautepierre - Hôpital Universitaire
        • Contact:
          • Christine MAUGARD, MD
        • Principal Investigator:
          • Christine MAUGARD, 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
      • Vandoeuvre les Nancy, France, 54511
        • Recruiting
        • CHU Nancy - Hôpital Brabois
        • Contact:
          • Jean-Marie RAVEL, MD
        • Principal Investigator:
          • Jean-Marie RAVEL, MD
      • Vandoeuvre les Nancy, France, 54511
        • Withdrawn
        • Centre Alexis Vautrin
      • Villejuif, France, 94805
        • Recruiting
        • Gustave Roussy
        • Contact:
          • Olivier CARON, MD
        • Principal Investigator:
          • Olivier CARON, MD
    • Haut De Seine
      • Saint-Cloud, Haut De Seine, France, 92210
        • Recruiting
        • Institut Curie - Hôpital René Huguenin
        • Contact:
        • Principal Investigator:
          • Emmanuelle FOURME, MD
    • Ile De France
      • Paris, Ile De France, France, 75005
        • Recruiting
        • Institut Curie
        • Contact:
        • Principal Investigator:
          • Dominique STOPPA-LYONNET, PU-PH
  • 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
  • Réunion
      • Saint-Pierre, Réunion, 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 gene variant class 3 or 4, present and selected in the families of national database of genetic group and cancer (GGC Unicancer) which identifies the variations of all genes from the panel of genes of all French laboratories.
  • 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, retained by investigators, based on family structure and degree of related compared to the index case
  • 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
Time Frame
Perform the co-segregation analysis of the selected VUS in the families in order to classify the maximum of variants in terms of their probability to be pathogenic
Time Frame: up to 15 years
up to 15 years

Secondary Outcome Measures

Outcome Measure
Time Frame
• Propose a standardized method to classify VUS that can be integrated into the already existing classification established in the UMD-BRCA1/2 database, with the main focus on variants of class 4 (probably causal) and class 3 (unknown significance).
Time Frame: up to 15 years
up to 15 years
• Maximize the number of VUS (both pathogenic and neutral) having associated recommendations for clinical management of at-risk relatives that can be used to guide genetic counselling.
Time Frame: up to 15 years
up to 15 years
Assess the penetrance of several class 3 and 4 VUS probably associated with moderate cancer risk, using collected phenotype/genotype data on extended pedigrees.
Time Frame: up to 15 years
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 Chair: Dominique STOPPA-LYONNET, PU-PH, Institut Curie
  • Study Director: Sandrine CAPUTO, 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.

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)

January 2, 2033

Study Completion (Estimated)

January 2, 2034

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)

January 17, 2024

Last Update Submitted That Met QC Criteria

January 16, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IC 2011-11

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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