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Aim: Studies evaluating the prognostic impact of germline BRCA1/2 mutations (gBRCAm) in patients with breast cancer report conflicting results. Therefore, we aimed to investigate outcomes of patients with gBRCA mutations and early onset of breast cancer (<30 years) compared with those of noncarriers., Materials and Methods: This retrospective study included 149 patients recruited between 2005 and 2019. The outcomes were overall survival (OS) and disease-free survival (DFS), which were defined as the time from the first diagnosis to death from any cause and the first recurrence, second cancer, or death from any cause, respectively. Key patient data, Kaplan-Meier plots, and outcomes were described according to the BRCA mutation status. Hazard ratios (HR) were calculated using the Cox proportional hazards model., Results: Twenty-eight patients (28/149; 18.8 %) were gBRCAm carriers. The OS median follow-up was 8.2 years. OS was 89.3% [70.4-96.4] in carriers vs 99.2% [95% CI: 94.3-99.9] in non-carrier patients at 2 years; 85.2% [65.2-94.2] vs 93.0% [86.5-96.5] at 5 years, and 76.5% [54.7-88.8] vs 85.2% [75.7-91.2] at 10 years. There was no difference in OS between groups in multivariable analysis (HR = 1.90 [0.69-5.23], p = 0.22). The DFS median follow-up was 6.6 years. Similar results were observed for DFS (HR = 1.39 [0.63-3.08], p = 0.42)., Conclusion: In this large hospital-based cohort of patients with very early-onset breast cancer, we found no clear evidence that gBRCA1/2m significantly affects OS after adjusting for known prognostic factors., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of interests D.S.-L. and the Institut Curie have received honoraria for her participation in education meetings organized by AstraZeneca or Tesaro. The remaining authors declare no conflict of interest., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)