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COsegregation of VARiants in the BRCA1/2 and PALB2 Genes (COVAR)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01689584
Recruitment Status : Recruiting
First Posted : September 21, 2012
Last Update Posted : December 16, 2020
Information provided by (Responsible Party):
Institut Curie

Brief 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.

Condition or disease Intervention/treatment Phase
Genes, BRCA1 Genes, BRCA2 Ovarian Neoplasms Breast Neoplasms Genes, PALB2 Genetic: salivary kit Not Applicable

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.

For PALB2, the gene was discovered in 2006. This PALB2 gene has been identified as a predisposition factor to breast cancer by a candidate gene approach. In a first step, the protein encoded by this PALB2 gene (PArtner and Localizer of BRCA2) was identified by a co-immunoprecipitation approach of BRCA2 and its different partners (Foulkes et al., 2007; Rahman et al., 2007). Xia et al., 2006). The association studies showed that monoallelic inactivating variants were more common in women with breast cancer group compared to the control group. A large study of 362 cases in eight countries confirmed the position of PALB2 (Antoniou et al., 2014). The risk of ovarian cancer is likely but not yet proven. This gene has been used for diagnosis in France since July 2015. The data collection is ongoing and the database under construction.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2000 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Study of Family COsegregation of VARiants in the BRCA1/2 and PALB2 Genes to Validate Their Use in Genetic
Actual Study Start Date : April 2012
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2027

Resource links provided by the National Library of Medicine

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

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. • 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 ]
  2. • 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 ]
  3. 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 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Index cases:

  • A person carrying a BRCA1 or BRCA2 or PALB2 variant class 3 or 4, present and selected in the families of UMD-BRCA1/2 or PALB2 national database of genetic group and cancer (GGC Unicancer) which identifies changes in BRCA1, BRCA2 and PALB2 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01689584

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Contact: Sandrine CAPUTO, PhD 33172389367
Contact: Isabelle TURBIEZ, Project Manager 33147111659

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Sponsors and Collaborators
Institut Curie
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Study Chair: Dominique STOPPA-LYONNET, PU-PH Institut Curie
Study Director: Sandrine CAPUTO, PhD Institut Curie
Additional Information:
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Responsible Party: Institut Curie Identifier: NCT01689584    
Other Study ID Numbers: IC 2011-11
First Posted: September 21, 2012    Key Record Dates
Last Update Posted: December 16, 2020
Last Verified: December 2020
Keywords provided by Institut Curie:
genetic counseling
Additional relevant MeSH terms:
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Breast Neoplasms
Ovarian Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders