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Characterization of the pathogenic mechanism of a novel BRCA2 variant in a Chinese family

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Abstract

Introduction: Germline mutations of BRCA1 and BRCA2 account for the majority of hereditary breast cancers, many of which are classified as variants of unknown significance (VUS). We report the identification of a novel BRCA2 variant (c.7806-9T > G) in a Chinese family with multiple breast cancers and document it as a pathogenic mutation. Methods: The proband in this family was diagnosed with breast cancer at age 50 with a strong family history of breast cancer. DNA and RNA were extracted from the blood of the proband and her family, and was used for BRCA gene mutation/deletion screening and RNA splicing analysis. Results: BRCA2 c.7806-9T > G was identified in the proband, which was suggestive of a variant. This change was also found in two sisters of the proband with a history of breast cancer, as well as from the proband’s maternal gastric cancer. The only sibling free of breast cancer did not carry the BRCA2 variant, thus demonstrating that the mutation segregates with the clinical phenotype in this family. RNA analysis on the proband blood sample revealed three aberrant splicing variants: c.7806_7874del, c.7806_7976del, and c.7806-8_7806-1ins. The latter causes a frameshift and creates a truncated protein, whilst the other two splicing variants resulted in shorter forms of the protein. Conclusions: The identified BRCA2 c.7806-9T > G [Genbank: DQ889340] was found to be pathogenic, based on aberrant splicing events resulting in the formation of truncated protein products. Thus, better understanding and classification of BRCA variants as neutral or disease causing has important implications for genetic counseling so that appropriate management can be given.

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Abbreviations

DCIS:

Ductal carcinoma in situ

MLPA:

Multiplex ligation-dependent probe amplification

PAGE:

Polacrylamide gel

RT-PCR:

Reverse-transcription polymerase chain reaction

VUS:

Variant of unknown significance

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Acknowledgements

We would like to thank Dr Walton WT Li, superintendent of the Hong Kong Sanatorium and Hospital and the Dr Ellen Li Charitable Foundation for their support of the Hong Kong hereditary and high-risk breast cancer programme.

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Authors and Affiliations

  1. Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA

    Ava Kwong

  2. Division of Breast Surgery, Department of Surgery, University of Hong Kong Medical Centre, Hong Kong, Hong Kong

    Ava Kwong

  3. Cancer Genetics Centre, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong

    Ava Kwong, L. P. Wong & E. S. K. Ma

  4. Division of Molecular Pathology, Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong

    L. P. Wong & E. S. K. Ma

  5. Department of Pathology, University of Hong Kong Medical Centre, Hong Kong, Hong Kong

    K. Y. K. Chan & U. S. Khoo

  6. Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA, USA

    J. M. Ford

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  1. Ava Kwong
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  2. L. P. Wong
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Correspondence to Ava Kwong.

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Kwong, A., Wong, L.P., Chan, K.Y.K. et al. Characterization of the pathogenic mechanism of a novel BRCA2 variant in a Chinese family. Familial Cancer 7, 125–133 (2008). https://doi.org/10.1007/s10689-007-9155-7

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  • DOI: https://doi.org/10.1007/s10689-007-9155-7

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