Up to 80% of BRCA1 and BRCA2 genetic variants remain of uncertain clinical significance (VUSs). Only variants classified as pathogenic or likely pathogenic can guide breast and ovarian cancer prevention measures and treatment by PARP inhibitors. We report the first results of the ongoing French national COVAR (cosegregation variant) study, the aim of which is to classify BRCA1/2 VUSs. The classification method was a multifactorial model combining different associations between VUSs and cancer, including cosegregation data. At this time, among the 653 variants selected, 101 (15%) distinct variants shared by 1,624 families were classified as pathogenic/likely pathogenic or benign/likely benign by the COVAR study. Sixty-six of the 101 (65%) variants classified by COVAR would have remained VUSs without cosegregation data. Of note, among the 34 variants classified as pathogenic by COVAR, 16 remained VUSs or likely pathogenic when following the ACMG/AMP variant classification guidelines. Although the initiation and organization of cosegregation analyses require a considerable effort, the growing number of available genetic tests results in an increasing number of families sharing a particular variant, and thereby increases the power of such analyses. Here we demonstrate that variant cosegregation analyses are a powerful tool for the classification of variants in the BRCA1/2 breast-ovarian cancer predisposition genes.

高达 80% 的BRCA1和BRCA2遗传变异仍具有不确定的临床意义 (VUS)。只有被归类为致病性或可能致病性的变异才能指导 PARP 抑制剂对乳腺癌和卵巢癌的预防措施和治疗。我们报告了正在进行的法国国家 COVAR（共分离变体）研究的第一个结果，其目的是对BRCA1/2进行分类VUS。分类方法是一个多因素模型，结合了 VUS 和癌症之间的不同关联，包括共分离数据。目前，在所选的 653 个变异中，1,624 个家族共有的 101 个（15%）不同变异被 COVAR 研究归类为致病性/可能致病性或良性/可能良性。COVAR 分类的 101 个 (65%) 变体中有 66 个在没有共分离数据的情况下仍然是 VUS。值得注意的是，在被 COVAR 归类为致病性的 34 种变异中，在遵循 ACMG/AMP 变异分类指南时，16 种仍然是 VUS 或可能致病。尽管共分离分析的启动和组织需要付出相当大的努力，但越来越多的可用基因测试导致越来越多的家庭共享特定变体，从而增加此类分析的能力。在这里，我们证明了变异共分离分析是对变异进行分类的强大工具。BRCA1/2乳腺癌-卵巢癌易感基因。