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

• 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 ] [ Designated as safety issue: No ]
  

• • 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 ] [ Designated as safety issue: No ]
  
• • 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 ] [ Designated as safety issue: No ]
  
• 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 ] [ Designated as safety issue: No ]
  

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.