Characterization of a novel germline BRCA1 splice variant, c.5332+4delA Journal Article


Authors: Yang, C.; Jairam, S.; Amoroso, K. A.; Robson, M. E.; Walsh, M. F.; Zhang, L.
Article Title: Characterization of a novel germline BRCA1 splice variant, c.5332+4delA
Abstract: Purpose: Germline mutations in BRCA1 and BRCA2 confer a significant increase in risk for cancer, and determining pathogenicity of a BRCA variant can guide the clinical management of the disease. About 1/3 of BRCA1 variants reported in the public databases have uncertain clinical significance due to lack of conclusive evidence. This study aims to characterize a novel BRCA1 deletion affecting the + 4 splice donor site identified in an individual with early-onset breast cancer. Methods: The effect of BRCA1 c.5332+4delA variant on RNA splicing was evaluated by amplifying regions of BRCA1 from cDNA derived from the patient. The proportion of abnormal transcript in the total transcripts was quantified. Loss of heterozygosity (LOH) in tumor tissue was investigated using Sanger sequencing and fragment analysis. Results: BRCA1 c.5332+4delA caused skipping of exon 21 in patient-derived samples. Semi-quantitative analysis indicated that this aberrant RT-PCR product accounts for about 40% of the total transcript levels. Loss of heterozygosity (LOH) was observed in patient’s tumor tissue. Conclusions: Our results indicate that the BRCA1 c.5332+4delA variant contributes to cancer predisposition through disruption of normal mRNA splicing. We classify this variant as likely pathogenic. © 2017, Springer Science+Business Media, LLC, part of Springer Nature.
Keywords: breast cancer; loss of heterozygosity; brca1; splicing; pathogenic; exon skipping; c.5332+4dela; germline variant
Journal Title: Breast Cancer Research and Treatment
Volume: 168
Issue: 2
ISSN: 0167-6806
Publisher: Springer  
Date Published: 2018-04-01
Start Page: 543
End Page: 550
Language: English
DOI: 10.1007/s10549-017-4595-8
PROVIDER: scopus
PUBMED: 29185120
DOI/URL:
Notes: Article -- Export Date: 2 April 2018 -- Source: Scopus
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MSK Authors
  1. Mark E Robson
    365 Robson
  2. Liying Zhang
    88 Zhang
  3. Michael Francis Walsh
    46 Walsh
  4. Ciyu   Yang
    8 Yang
  5. Sowmya Jairam
    6 Jairam