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COsegregation of VARiants in the BRCA1/2 Genes
Conditions
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
Interventional
Study Phase
N/A
Study Design
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic
Intervention
Name: salivary kit
Type: Genetic
Overall Status
Recruiting
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.
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.
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
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
Locations
CHU de Pointe à Pitre
Pointe à Pitre, Guadeloupe, France
Institut Curie - Hopital Rene Huguenin
Status: Recruiting
Saint-Cloud, Haut de Seine, France
Institut Curie
Status: Recruiting
Contact: Sandrine CAPUTO, PhD - 33147112309 - sandrine.caputo@curie.net
Paris, Ile de France, France
CHU de Fort de France
Status: Recruiting
Contact: Dominique STOPPA-LYONNET, PU-PH - 33144324694 - dominique.stoppa-lyonnet@curie.net
Fort de France, Martinique, France
ICO - Centre Paul Papin
Status: Recruiting
Angers, France
Institut Sainte-Catherine
Status: Recruiting
Avignon, France
CHU Besançon
Status: Recruiting
Besancon, France
Institut Bergonié
Status: Recruiting
Bordeaux, France
Centre Hospitalier Jacques Coeur
Status: Recruiting
Bourges, France
CHU Morvan de Brest
Status: Recruiting
Brest, France
Centre François Baclesse
Status: Recruiting
Caen, France
Centre Hospitalier Hôtel Dieu
Status: Recruiting
Chambery, France
Centre Jean Perrin
Status: Recruiting
Clermont-Ferrand, France
Hôpital Civil de Colmar
Status: Recruiting
Colmar, France
CHU de Dijon
Status: Recruiting
Dijon, France
CHU de Grenoble
Status: Recruiting
Grenoble, France
Centre Hospitalier Saint-Louis
Status: Recruiting
La Rochelle, France
Hôpital Flaubert
Status: Recruiting
Le Havre, France
Centre Oscar Lambret
Status: Recruiting
Lille, France
Chru Lille
Status: Recruiting
Lille, France
CHU Dupuytren
Status: Recruiting
Limoges, France
Centre Léon Bérard
Status: Recruiting
Lyon, France
Hospices Civils de Lyon
Status: Recruiting
Lyon, France
CHU La Timone
Status: Recruiting
Marseille, France
CRLCC Val d'Aurelle
Status: Recruiting
Montpellier, France
Centre Catherine de Sienne
Status: Recruiting
Nantes, France
Centre Antoine Lacassagne
Status: Recruiting
Nice, France
Centre Hospitalier de Niort
Status: Recruiting
Niort, France
CHRU Caremeau
Status: Recruiting
Nîmes, France
Hôpital de la Source
Status: Recruiting
Orléans, France
Groupe Hospitalier Pitié-Salpêtrière
Status: Recruiting
Paris, France
Hôpital Tenon
Status: Recruiting
Paris, France
CHU La Milétrie
Status: Recruiting
Poitiers, France
Institut Jean Godinot
Status: Recruiting
Reims, France
Centre Eugène Marquis
Status: Recruiting
Rennes, France
CHU de Rouen
Status: Recruiting
Rouen, France
CHU Saint Etienne
Status: Recruiting
Saint Priest en Jarez, France
ICO - Centre René Gauducheau
Status: Recruiting
Saint-Herblain, France
Centre Hospitalier d'Angoulème
Status: Recruiting
Saint-michel, France
Centre Paul Strauss
Status: Recruiting
Stransbourg, France
Hopital Universitaire
Status: Recruiting
Strasbourg, France
Institut Claudius Regaud
Status: Recruiting
Toulouse, France
CHU Bretonneau
Status: Recruiting
Tours, France
Centre Alexis Vautrin
Status: Recruiting
Vandoeuvre les Nancy, France
Institut Gustave Roussy
Status: Recruiting
Villejuif, France
Status: Recruiting
Start Date
April 2012
Completion Date
December 2027
Sponsors
Institut Curie
Source
Institut Curie
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page