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Impact of proactive high-throughput functional assay data on BRCA1 variant interpretation in 3684 patients with breast or ovarian cancer

Journal of Human Genetics volume 65, pages 209–220 (2020)Cite this article

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Abstract

The clinical utility of BRCA1/2 genotyping was recently extended from the selection of subjects at high risk for hereditary breast and ovary cancer to the identification of candidates for poly (ADP-ribose) polymerase (PARP) inhibitor treatment. This underscores the importance of accurate interpretation of BRCA1/2 genetic variants and of reducing the number of variants of uncertain significance (VUSs). Two recent studies by Findlay et al. and Starita et al. introduced high-throughput functional assays, and proactively analyzed variants in specific regions regardless of whether they had been previously observed. We retrospectively reviewed all BRCA1 and BRCA2 germline genetic test reports from patients with breast or ovarian cancer examined at Asan Medical Center (Seoul, Korea) between September 2011 and December 2018. Variants were assigned pathogenic or benign strong evidence codes according to the functional classification and were reclassified according to the ACMG/AMP 2015 guidelines. Among 3684 patients with available BRCA1 and BRCA2 germline genetic test reports, 429 unique variants (181 from BRCA1) were identified. Of 34 BRCA1 variants intersecting with the data reported by Findlay et al., three missense single-nucleotide variants from four patients (0.11%, 4/3684) were reclassified from VUSs to likely pathogenic variants. Four variants scored as functional were reclassified into benign or likely benign variants. Three variants that overlapped with the data reported by Starita et al. could not be reclassified. In conclusion, proactive high-throughput functional study data are useful for the reclassification of clinically observed VUSs. Integrating additional evidence, including functional assay results, may help reduce the number of VUSs.

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Acknowledgements

We would like to thank Asan Medical Library for the paper formatting.

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  1. These authors contributed equally: Jong Won Lee, Woochang Lee

Authors and Affiliations

  1. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea

    Hyun-Ki Kim, Woochang Lee, Sail Chun & Won-Ki Min

  2. Department of Laboratory Medicine, Hallym University College of Medicine, Dongtan Sacred Heart Hospital, Hwaseong, Republic of Korea

    Eun Jin Lee

  3. Department of Obstetrics and Gynecology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea

    Young-Jae Lee, Shin-Wha Lee & Yong-Man Kim

  4. Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea

    Jisun Kim, Young Joo Lee, Jong Won Lee, Byung Ho Son & Sei-Hyun Ahn

  5. Department of Biomedical Sciences, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Yongsub Kim, Kyunggon Kim & Suhwan Chang

  6. Department of Oncology, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea

    Kyung Hae Jung

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Kim, HK., Lee, E.J., Lee, YJ. et al. Impact of proactive high-throughput functional assay data on BRCA1 variant interpretation in 3684 patients with breast or ovarian cancer. J Hum Genet 65, 209–220 (2020). https://doi.org/10.1038/s10038-019-0713-2

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