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Variants of Uncertain Significances in Hereditary Breast and Ovarian Cancer

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Hereditary Breast and Ovarian Cancer

Abstract

Hereditary breast and ovarian cancer syndrome is a BRCA1- or BRCA2-linked genetic disorder associated with a high risk of developing breast, ovarian, and other cancers. Detection of a BRCA1 or BRCA2 pathogenic variants by genetic testing triggers several clinical management approaches, such as surveillance and prophylactic surgery for healthy carriers, and chemotherapy using poly (ADP-ribose) polymerase (PARP) inhibitors for patients with cancer. Therefore, accurate diagnoses are critical for clinical decision-making and improvement of prognosis.

BRCA1 and BRCA2 variants, whose pathogenicity can be inferred from the genetic code, are classified as pathogenic, likely pathogenic, variants of uncertain significance (VUS), likely benign, or benign. Most variants established to be pathogenic are premature truncation variants, including nonsense or frameshift alterations. VUS are primarily missense and splicing variants and are sequence changes whose impact on function cannot be inferred. Recently, next-generation sequencing has been broadly applied in research and clinical diagnostics to aid both basic research and clinical patient management, where it has led to identification of a vast number of VUS that require interpretation. The pathogenicity of VUS can be evaluated by multifactorial likelihood models that use personal and family history of cancer, segregation data, functional assays, and in silico prediction tools.

Here, we focus on classification of variants in BRCA1 and BRCA2, and the use of functional assays in attempts to classify VUS, with the aim of improving the clinical management and prognosis of carriers and patients.

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Authors and Affiliations

  1. Department of Cancer Biology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Sendai, Japan

    Yuki Yoshino & Natsuko Chiba

  2. Laboratory of Cancer Biology, Graduate School of Life Sciences, Tohoku University, Sendai, Japan

    Yuki Yoshino & Natsuko Chiba

  3. Department of Cancer Biology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Yuki Yoshino & Natsuko Chiba

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  1. Yuki Yoshino
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  2. Natsuko Chiba
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Correspondence to Natsuko Chiba .

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Editors and Affiliations

  1. Department of Breast Surgical Oncology, Showa University, School of Medicine, Tokyo, Japan

    Seigo Nakamura

  2. Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan

    Daisuke Aoki

  3. Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    Yoshio Miki

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Yoshino, Y., Chiba, N. (2021). Variants of Uncertain Significances in Hereditary Breast and Ovarian Cancer. In: Nakamura, S., Aoki, D., Miki, Y. (eds) Hereditary Breast and Ovarian Cancer . Springer, Singapore. https://doi.org/10.1007/978-981-16-4521-1_4

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