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Study of Family COsegregation of VARiants in the BRCA1/2 Genes to Validate Their Use in Genetic

18 Years
Open (Enrolling)
Genes, BRCA1, Genes, BRCA2, Ovarian Neoplasms, Breast Neoplasms

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Trial Information

Study of Family COsegregation of VARiants in the BRCA1/2 Genes to Validate Their Use in Genetic

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

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

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Outcome Measure:

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

Outcome Time Frame:

up to 15 years

Safety Issue:


Principal Investigator


Investigator Role:

Principal Investigator

Investigator Affiliation:

Institut Curie


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:

IC 2011-11



Start Date:

April 2012

Completion Date:

December 2027

Related Keywords:

  • Genes, BRCA1
  • Genes, BRCA2
  • Ovarian Neoplasms
  • Breast Neoplasms
  • BRCA1
  • BRCA2
  • VUS
  • co-segregation
  • genetic counseling
  • Breast Neoplasms
  • Neoplasms
  • Ovarian Neoplasms