An interventional study of salivary kit in Gene Mutation-Related Cancer and Genetic Predisposition, sponsored by Institut Curie. Recruiting at 62 sites in 5 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-09-01.
Sponsored by Institut Curie · Not applicable, Interventional, and Diagnostic
The aim of the COVAR project is to achieve reliable classification of as many variants of interest as possible from the French OncoGenetics Database (FrOG, https://frog-db.fr/) 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.
Originally, the COVAR study was designed to investigate 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. Over time, it has evolved alongside advances in genetic diagnostics. First, it incorporated the Partner and Localizer of BRCA2 (PALB2) gene, included in routine testing since 2015, and more recently it has expanded to include all genes analyzed in multigene panels for families suspected of hereditary cancer predisposition syndromes.
To support variant interpretation, national databases have been developed. The Universal Mutation DataBase BRCA1/BRCA2 (UMD-BRCA1/BRCA2), maintained within the French oncogenetics network, collects anonymized genetic data and enables the identification of families sharing the same variants. More recently, the FrOG database (established in 2020) has expanded this approach to 38 genes and over 66,000 families, compiling nearly 20,000 distinct variants, including thousands of VUS and likely pathogenic variants.
As knowledge has progressed, classification systems have evolved. The term VUS now strictly refers to class 3 variants, while class 4 (likely pathogenic) variants are increasingly actionable in clinical care under certain conditions. Additionally, a subset of class 5 variants with intermediate effects ("hypomorphic" variants) has been recognized, highlighting variability in risk depending on the type of genetic alteration. These variants are now included in COVAR to refine risk estimates.
One of the key measurable parameters for classification of variants of interest 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 pathogenicity of a given variant. The main objective of the COVAR study (COsegregation VARiants) is to organize such co-segregation studies using national database data, in order to determine the pathogenicity of selected variants and improve 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 (class 3). 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.
For class 4 and hypomorphic class 5 variants, relatives are advised to attend oncogenetic consultations for targeted diagnostic testing without additional sampling. Genetic analyses for class 3 variants are conducted by the identifying laboratory, while classes 4-5 analyses are performed by affiliated GGC laboratories.
Results are sent anonymously to the coordinating center for statistical analysis, and only overall variant classification (not individual results) is communicated back.
If a variant is found pathogenic, the index case is informed, enabling family communication, possible presymptomatic testing (class 3), and potential clinical management impact (classes 4-5).
241 studies on the registry are indexed under Genetic Predisposition to Disease; 95 are open to participants now.
This study's planned enrollment of 11,000 is above the median of 250 across 85 interventional studies indexed under Genetic Predisposition to Disease.
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You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Genetic: salivary kit
The saliva samples will be made of selected related (DNA).
Perform the co-segregation analysis of the selected VUS (class 3) or likely pathogenic variant (class 4) in the families.
Number of variants classified using methods based on likelihood ratio estimation of the selected VUS (class 3) or likely pathogenic variant (class 4) in the families in order to classify the maximum of variants in terms of their probability to be pathogenic (class 5) or (likely) benign (class 1 and 2).
Time frame: up to 15 years
Propose a standardized method to classify as many variants as possible from the national of the Genetics and Cancer Group (GGC) of Unicancer.
Provision of variant classifications to laboratories by the expert group based on the national FrOG database, along with harmonization of the conclusions regarding these variants.
Time frame: up to 15 years
Maximize the number of VUS (class 3) or likely pathogene (class 4) having associated recommendations for clinical management of at-risk relatives that can be used to guide genetic counselling.
Number of VUS (class 3) or likely pathogene (class 4) classified to guide genetic counselling
Time frame: up to 15 years
Assess the penetrance of selected variants of interest, particularly hypomorphic pathogenic variant (hypomorphic class 5) shared across multiple families.
Number of new hypomorphic variants and determination of their penetrance.
Time frame: up to 15 years
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