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Breast Cancer Res Treat. 2016 Jan;155(2):253-60. doi: 10.1007/s10549-015-3676-9. Epub 2016 Jan 16.

Investigating the effect of 28 BRCA1 and BRCA2 mutations on their related transcribed mRNA.

Author information

1
Hereditary Cancer Program, Molecular Diagnostics Unit, Catalan Institute of Oncology (ICO-IDIBELL), Hospital Duran i Reynals, Gran Via 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain.
2
Molecular Biology Laboratory, Service of Clinical Analysis, University and Polytechnic Hospital La Fe, Valencia, Spain.
3
Genètica Molecular, Laboratorio Echevarne, Barcelona, Spain.
4
Hereditary Cancer Program, Molecular Diagnostics Unit, Catalan Institute of Oncology (ICO-IDIBELL), Hospital Duran i Reynals, Gran Via 199, L'Hospitalet de Llobregat, 08908, Barcelona, Spain. conxi.lazaro@gmail.com.

Abstract

Germline inactivating mutations in the BRCA1 and BRCA2 genes are responsible for hereditary breast and ovarian cancer syndrome (HBOCS). Genetic testing of these genes identifies a significant proportion of variants of uncertain significance (VUS). Elucidation of the clinical impact of these variants is an important challenge in genetic diagnostics and counseling. In this study, we assess the RNA effect of 28 BRCA1 and BRCA2 VUS identified in our set of HBOCS families with the aim of gaining insight into their clinical relevance. mRNA was extracted from VUS carriers and controls lymphocytes cultured for 5-6 days and treated with puromycin. RNA was reverse transcribed to perform transcriptional analysis for the study of splicing aberrations. In silico prediction tools were used to select those variants most likely to affect the RNA splicing process. Six out of the 28 variants analyzed showed an aberrant splicing pattern and could therefore be classified as probably pathogenic mutations. Reclassification of VUS improves the genetic counseling and clinical surveillance of carriers of these mutations and highlights the importance of RNA studies in routine diagnostic laboratories.

KEYWORDS:

BRCA1; BRCA2; RNA; Splicing; VUS

PMID:
26780556
DOI:
10.1007/s10549-015-3676-9
[Indexed for MEDLINE]

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