Splicing analysis of 14 BRCA1 missense variants classifies nine variants as pathogenic

Breast Cancer Research and Treatment
Lise B AhlbornThomas V O Hansen

Abstract

Pathogenic germline mutations in the BRCA1 gene predispose carriers to early onset breast and ovarian cancer. Clinical genetic screening of BRCA1 often reveals variants with uncertain clinical significance, complicating patient and family management. Therefore, functional examinations are urgently needed to classify whether these uncertain variants are pathogenic or benign. In this study, we investigated 14 BRCA1 variants by in silico splicing analysis and mini-gene splicing assay. All 14 alterations were missense variants located within the BRCT domain of BRCA1 and had previously been examined by functional analysis at the protein level. Results from a validated mini-gene splicing assay indicated that nine BRCA1 variants resulted in splicing aberrations leading to truncated transcripts and thus can be considered pathogenic (c.4987A>T/p.Met1663Leu, c.4988T>A/p.Met1663Lys, c.5072C>T/p.Thr1691Ile, c.5074G>C/p.Asp1692His, c.5074G>A/p.Asp1692Asn, c.5074G>T/p.Asp1692Tyr, c.5332G>A/p.Asp1778Asn, c.5332G>T/p.Asp1778Tyr, and c.5408G>C/p.Gly1803Ala), whereas five BRCA1 variants had no effect on splicing (c.4985T>C/p.Phe1662Ser, c.5072C>A/p.Thr1691Lys, c.5153G>C/p.Trp1718Ser, c.5154G>T/p.Trp1718Cys, and c.5333A>G/p.Asp1778Gly). Eight of ...Continue Reading

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Citations

Apr 29, 2015·Breast Cancer Research and Treatment·Ji WenXiaodong Cai
Jun 10, 2016·Hereditary Cancer in Clinical Practice·Marc BennedbækThomas V O Hansen
Oct 14, 2016·Journal of Human Genetics·Maria RossingThomas vO Hansen
Jan 23, 2018·Genetic Testing and Molecular Biomarkers·Julie DutilMiguel Echenique
Dec 13, 2017·Vox Sanguinis·A H LaursenK Magnussen
Jun 18, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Peter BouwmanJos Jonkers
Dec 21, 2020·Blood Cells, Molecules & Diseases·Marlène Le TertreGérald Le Gac
Oct 23, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Paulo C M LyraAlvaro N A Monteiro

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Methods Mentioned

BETA
electrophoresis
PCR

Software Mentioned

Image Lab
GeneSplicer
Human Splicing Finder
Splice Site Finder
MaxEntScan
NNSplice
SpliceSiteFinder
ENIGMA
Alamut

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