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Familial Cancer

, Volume 7, Issue 2, pp 125–133 | Cite as

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

  • Ava Kwong
  • L. P. Wong
  • K. Y. K. Chan
  • E. S. K. Ma
  • U. S. Khoo
  • J. M. Ford
Article

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.

Keywords

BRCA1 BRCA2 Chinese breast cancer Variant of unknown significance VUS 

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

Notes

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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Copyright information

© Springer Science + Business Media B.V. 2007

Authors and Affiliations

  • Ava Kwong
    • 1
    • 2
    • 3
  • L. P. Wong
    • 3
    • 4
  • K. Y. K. Chan
    • 5
  • E. S. K. Ma
    • 3
    • 4
  • U. S. Khoo
    • 5
  • J. M. Ford
    • 6
  1. 1.Department of SurgeryStanford University School of MedicineStanfordUSA
  2. 2.Division of Breast Surgery, Department of SurgeryUniversity of Hong Kong Medical CentreHong KongHong Kong
  3. 3.Cancer Genetics CentreHong Kong Sanatorium and HospitalHong KongHong Kong
  4. 4.Division of Molecular Pathology, Department of PathologyHong Kong Sanatorium and HospitalHong KongHong Kong
  5. 5.Department of PathologyUniversity of Hong Kong Medical CentreHong KongHong Kong
  6. 6.Departments of Medicine and GeneticsStanford University School of MedicineStanfordUSA

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