COsegregation of VARiants in Panel of Genes

Genetic Predisposition Clinical Trial

— COVAR  

Official title:

Study of Family COsegregation of Nucleotide VARiants in the Panel of Genes to Validate Their Use in Genetic Counseling

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01689584
• Other study ID #: IC 2011-11
• Status: Recruiting
• Phase: N/A
• Start date: July 2, 2012
• Est. completion date: January 2, 2034

Study information

• Verified date: January 2024
• Source: Institut Curie
• Contact: Sandrine CAPUTO, PhD
• Phone: 33172389367
• Email: sandrine.caputo[@]curie.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 3500
• Est. completion date: January 2, 2034
• Est. primary completion date: January 2, 2033
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Gene Mutation-Related Cancer
• Genetic Predisposition
• Genetic Predisposition to Disease

Intervention

Genetic:
• salivary kit
The saliva samples will be made of selected related (DNA).

Locations

Country	Name	City	State
France	CHU Amiens - Hôpital Nord	Amiens
France	ICO - Centre Paul Papin	Angers
France	Centre Hospitalier d'Angoulème	Angoulême
France	Institut Sainte-Catherine	Avignon
France	CHU Besançon	Besancon
France	Groupe Hospitalier Pellegrin	Bordeaux
France	Institut Bergonié	Bordeaux
France	Centre Hospitalier Jacques Coeur	Bourges
France	CHU Morvan de Brest	Brest
France	Centre François Baclesse	Caen
France	Centre Hospitalier Hôtel Dieu	Chambery
France	Centre Jean Perrin	Clermont-Ferrand
France	Hôpital Civil de Colmar	Colmar
France	CHU de Dijon	Dijon
France	CHU de Grenoble	Grenoble
France	Groupe Hospitalier La Rochelle-Ré-Aunis	La Rochelle
France	Hôpital Flaubert	Le Havre
France	Centre Oscar Lambret	Lille
France	Chru Lille	Lille
France	CHU Dupuytren	Limoges
France	Centre Léon Bérard	Lyon
France	Hospices Civils de Lyon	Lyon
France	CHU La Timone	Marseille
France	Institut Paoli Calmettes	Marseille
France	CHU Arnaud de Villeneuve	Montpellier
France	Centre Catherine de Sienne	Nantes
France	Centre Antoine Lacassagne	Nice
France	CHRU Caremeau	Nîmes
France	Centre Hospitalier Georges Renon	Niort
France	Hôpital de la Source	Orléans
France	Groupe Hospitalier Pitié-Salpêtrière	Paris
France	HEGP	Paris
France	Hôpital Saint-Antoine	Paris
France	Hôpital Saint-Louis	Paris
France	Hôpital Tenon	Paris
France	Institut Curie	Paris	Ile De France
France	CHU La Milétrie	Poitiers
France	CHU de Reims	Reims
France	ICC Courlancy	Reims
France	Institut Jean Godinot	Reims
France	Centre Eugène Marquis	Rennes
France	CHU de Rouen	Rouen
France	Institut Curie - Hopital Rene Huguenin	Saint-Cloud	Haut De Seine
France	CHU Saint Etienne	Saint-Étienne
France	ICO - Centre René Gauducheau	Saint-Herblain
France	Hopital de Hautepierre - Hôpital Universitaire	Strasbourg
France	Institut de Cancérologie Strasbourg Europe ICANS	Strasbourg
France	Institut Claudius Regaud - IUCT - Oncopole	Toulouse
France	CHU Bretonneau	Tours
France	CH Simone VEIL	Troyes
France	Centre Hospitalier de Valence	Valence
France	Centre Alexis Vautrin	Vandoeuvre les Nancy
France	CHU Nancy - Hôpital Brabois	Vandoeuvre les Nancy
France	Gustave Roussy	Villejuif
Guadeloupe	CHU de Pointe à Pitre	Pointe à Pitre
Martinique	CHU de Fort de France	Fort de France
Réunion	CHU Sud Réunion Saint-Pierre	Saint-Pierre

Sponsors (1)

Lead Sponsor	Collaborator
Institut Curie

Countries where clinical trial is conducted

France,  Guadeloupe,  Martinique,  Réunion, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		up to 15 years
Secondary	• 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).		up to 15 years
Secondary	• 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.		up to 15 years
Secondary	Assess the penetrance of several class 3 and 4 VUS probably associated with moderate cancer risk, using collected phenotype/genotype data on extended pedigrees.		up to 15 years

External Links

•   French BRCA1 database
•   French BRCA2 database