Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer


Characterizing the pathogenicity of BRCA1 variants of uncertain significance (VUSs) is a major bottleneck in clinical management of BRCA1-associated breast cancer. Saturation genome editing (SGE) was recently reported as an innovative laboratory-based approach to assess the pathogenicity of BRCA1 variants. We combined clinical phenotypes and SGE score to identify the pathogenicity of BRCA1 VUSs detected in a cohort of 8,085 breast cancer patients. According to SGE function score, 33 out of 144 BRCA1 VUSs detected were classified into “loss of function” (n = 13), “intermediate” (n = 2), and “functional” (n = 18) groups. Compared with non-carriers, “loss of function” VUS carriers (n = 19) presented significantly worse clinicopathological characteristics. These included younger age at breast cancer diagnosis (44.4 years vs. 51.2 years, P = 0.01), stronger family history of any cancer (57.9% vs. 32.3%, P = 0.017) especially breast or ovarian cancer (47.4% vs. 9.3%, P < 0.001), more bilateral breast cancer (31.6% vs. 3.4%, P < 0.001), and triple-negative breast cancer (47.4% vs. 12.8%, P < 0.001), which were comparable to those of pathogenic variant carriers. In contrast, the clinical phenotypes of “functional” VUS carriers were similar to those of non-carriers. These results indicated that SGE was a reliable method in BRCA1 variant classification. Combining SGE function score and the available evidence, twelve out of 33 BRCA1 VUSs were reclassified as pathogenic or likely pathogenic variants and one was benign.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.


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We thank Berry Genomics (Beijing) for kind help with the multigene panel testing in this study.


This study was funded by the National Natural Science Foundation of China (81772824) and the Science Foundation of Peking University Cancer Hospital (2017-8).

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All authors contributed to the study conception and design. This study was designed by Yuntao Xie. Material preparation, data collection and analysis were performed by Qiting Wan, Li Hu, Ye Xu, Tao Ouyang, Jinfeng Li, Tianfeng Wang, Zhaoqing Fan, Tie Fan, Benyao Lin. The manuscript was revised by Ye Xu and Yuntao Xie. All authors commented on previous versions of the manuscript and approved the final manuscript.

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Correspondence to Ye Xu or Yuntao Xie.

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This study was reviewed and approved by the Ethics Committee of Peking University Cancer Hospital (No. 2011KT12).

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Wan, Q., Hu, L., Ouyang, T. et al. Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer. Familial Cancer (2020).

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  • BRCA1
  • Variants of uncertain significance
  • Saturation genome editing
  • Breast cancer
  • Clinical phenotype