COsegregation of VARiants in the BRCA1/2 Genes
Genes, BRCA1 - Genes, BRCA2 - Ovarian Neoplasms - Breast Neoplasms
Conditions: official terms
Breast Neoplasms - Neoplasms - Ovarian Neoplasms
Conditions: Keywords
BRCA1, BRCA2, VUS, co-segregation, genetic counseling
Study Type
Study Phase
Study Design
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
Name: salivary kit
Type: Genetic
Overall Status
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.
Detailed Description
The BRCA1 and BRCA2 genes are the two major high-risk breast and/or ovarian cancer susceptibility genes. Monoallelic germline mutations that disrupt their normal gene function significantly increase the risk of developing cancer in carriers. The identification of a causal mutation in a proband allows proposing pre-symptomatic testing for the causal mutation to all at-risk relatives. Currently, a causal mutation, used for genetic counseling, is presented in approximatively 13% of families tested. Variants of unknown biological significance (VUS) are detected in more than 20% of proband tested. For the families of these probands, genetic testing could not be proposed to relatives and the genetic counseling is guided by family history and epidemiological knowledges exclusively.

The French UMD-BRCA1/2 database, 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. One of the key measurable parameters for classification of VUS as causal mutations is their co-segregation with the disease. As 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.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: Inclusion Criteria:

Index cases:

- A person carrying a BRCA1 or BRCA2 variant class 3 or 4, this at least three different families in the national database UMD-BRCA1/2, national database of genetic group and cancer (GGC Unicancer) which identifies changes in BRCA1 and BRCA2 genes of all French laboratories.

- Age ≥ 18 years.

- Signed written inform consent "index case"

Related parties:

- Everything related to an index case, diagnosed with breast cancer or ovarian cancer.

- Any related case of a free index, selected by the investigators, according to family structure and the degree of related compared to the index case

- Age ≥ 18 years

- Signed written inform consent "Related selected"

Exclusion Criteria:

- Minors

- Persons deprived of liberty or under guardianship (including curators).

- Absence of signed written inform consent
CHU de Pointe à Pitre
Pointe à Pitre, Guadeloupe, France
Status: Recruiting
Institut Curie - Hopital Rene Huguenin
Saint-Cloud, Haut de Seine, France
Status: Recruiting
Contact: Sandrine CAPUTO, PhD - 33147112309 -
Institut Curie
Paris, Ile de France, France
Status: Recruiting
Contact: Dominique STOPPA-LYONNET, PU-PH - 33144324694 -
CHU de Fort de France
Fort de France, Martinique, France
Status: Recruiting
ICO - Centre Paul Papin
Angers, France
Status: Recruiting
Institut Sainte-Catherine
Avignon, France
Status: Recruiting
CHU Besançon
Besancon, France
Status: Recruiting
Institut Bergonié
Bordeaux, France
Status: Recruiting
Centre Hospitalier Jacques Coeur
Bourges, France
Status: Recruiting
CHU Morvan de Brest
Brest, France
Status: Recruiting
Centre François Baclesse
Caen, France
Status: Recruiting
Centre Hospitalier Hôtel Dieu
Chambery, France
Status: Recruiting
Centre Jean Perrin
Clermont-Ferrand, France
Status: Recruiting
Hôpital Civil de Colmar
Colmar, France
Status: Recruiting
CHU de Dijon
Dijon, France
Status: Recruiting
CHU de Grenoble
Grenoble, France
Status: Recruiting
Centre Hospitalier Saint-Louis
La Rochelle, France
Status: Recruiting
Hôpital Flaubert
Le Havre, France
Status: Recruiting
Centre Oscar Lambret
Lille, France
Status: Recruiting
Chru Lille
Lille, France
Status: Recruiting
CHU Dupuytren
Limoges, France
Status: Recruiting
Centre Léon Bérard
Lyon, France
Status: Recruiting
Hospices Civils de Lyon
Lyon, France
Status: Recruiting
CHU La Timone
Marseille, France
Status: Recruiting
CRLCC Val d'Aurelle
Montpellier, France
Status: Recruiting
Centre Catherine de Sienne
Nantes, France
Status: Recruiting
Centre Antoine Lacassagne
Nice, France
Status: Recruiting
Centre Hospitalier de Niort
Niort, France
Status: Recruiting
CHRU Caremeau
Nîmes, France
Status: Recruiting
Hôpital de la Source
Orléans, France
Status: Recruiting
Groupe Hospitalier Pitié-Salpêtrière
Paris, France
Status: Recruiting
Hôpital Tenon
Paris, France
Status: Recruiting
CHU La Milétrie
Poitiers, France
Status: Recruiting
Institut Jean Godinot
Reims, France
Status: Recruiting
Centre Eugène Marquis
Rennes, France
Status: Recruiting
CHU de Rouen
Rouen, France
Status: Recruiting
CHU Saint Etienne
Saint Priest en Jarez, France
Status: Recruiting
ICO - Centre René Gauducheau
Saint-Herblain, France
Status: Recruiting
Centre Hospitalier d'Angoulème
Saint-michel, France
Status: Recruiting
Centre Paul Strauss
Stransbourg, France
Status: Recruiting
Hopital Universitaire
Strasbourg, France
Status: Recruiting
Institut Claudius Regaud
Toulouse, France
Status: Recruiting
CHU Bretonneau
Tours, France
Status: Recruiting
Centre Alexis Vautrin
Vandoeuvre les Nancy, France
Status: Recruiting
Institut Gustave Roussy
Villejuif, France
Status: Recruiting
Start Date
April 2012
Completion Date
December 2027
Institut Curie
Institut Curie
Record processing date processed this data on July 28, 2015 page