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
References
Oct 7, 1994·Science·Y MikiW Ding
Feb 6, 1998·Human Mutation·J T BergthorssonR B Barkardottir
Aug 3, 2000·Human Mutation·C SzaboL C Brody
Feb 7, 2001·Human Molecular Genetics·J Vallon-ChristerssonA N Monteiro
Mar 20, 2001·Journal of Molecular Biology·D Chasman, R M Adams
Mar 16, 2002·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Thomas S FrankGregory C Critchfield
Apr 5, 2003·American Journal of Human Genetics·A AntoniouD F Easton
Oct 25, 2003·Science·Mary-Claire KingUNKNOWN New York Breast Cancer Study Group
May 11, 2004·Nature Structural & Molecular Biology·R Scott WilliamsJ N Mark Glover
Jul 6, 2004·Journal of Medical Genetics·V AbkevichS V Tavtigian
Jun 1, 2005·Journal of Medical Genetics·P K LovelockUNKNOWN kConFab Investigators
Feb 21, 2006·Cancer Research·Georgia Chenevix-TrenchUNKNOWN kConFab Investigators
Oct 26, 2006·Proteins·Craig A GoughTadashi Imanishi
Feb 20, 2007·PLoS Computational Biology·Rachel KarchinAndrej Sali
Oct 10, 2007·American Journal of Human Genetics·Douglas F EastonDavid E Goldgar
Apr 22, 2008·Journal of Medical Genetics·C BonnetM Tosi
Oct 28, 2008·Human Mutation·Amanda B SpurdleUNKNOWN IARC Unclassified Genetic Variants Working Group
Aug 4, 2009·EMBO Reports·Diana BaralleEmanuele Buratti
Mar 6, 2010·Breast Cancer Research and Treatment·Dorina M van der KolkJan C Oosterwijk
Mar 11, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David J SanzEladio A Velasco
Apr 10, 2010·The Journal of Biological Chemistry·Pamela J E RowlingLaura S Itzhaki
Jun 3, 2010·Cancer Research·Megan S LeeJ N Mark Glover
Jun 16, 2011·European Journal of Human Genetics : EJHG·Jean Christophe ThéryMario Tosi
Jul 20, 2011·Breast Cancer Research and Treatment·Mads ThomassenAna Vega
Oct 13, 2011·Human Mutation·Amanda B SpurdleUNKNOWN ENIGMA
Jan 27, 2012·Journal of Human Genetics·Wen-Hong KuoKing-Jen Chang
Apr 17, 2012·Human Mutation·Claude HoudayerDominique Stoppa-Lyonnet
Dec 15, 2012·PloS One·Barbara WappenschmidtRita K Schmutzler
Mar 2, 2013·PloS One·Mara ColomboPaolo Radice
May 1, 2013·Journal of the National Cancer Institute·Nasim MavaddatUNKNOWN EMBRACE
Jul 31, 2013·Human Mutation·Logan C WalkerUNKNOWN ENIGMA consortium
Feb 27, 2014·Human Molecular Genetics·Mara ColomboMiguel De La Hoya
Mar 29, 2014·European Journal of Human Genetics : EJHG·Ane Y SteffensenThomas vO Hansen
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
Feb 26, 2016·Human Mutation·Maxime P ValléeSean V Tavtigian
Oct 14, 2016·Journal of Human Genetics·Maria RossingThomas vO Hansen
Aug 5, 2017·Gene Therapy·H WuZ Liang
Jan 23, 2018·Genetic Testing and Molecular Biomarkers·Julie DutilMiguel Echenique
Nov 19, 2019·Frontiers in Genetics·Lulu LiXiuli Zhao
May 19, 2018·Frontiers in Oncology·Vanessa L LattimoreLogan C Walker
Dec 13, 2017·Vox Sanguinis·A H LaursenK Magnussen
May 16, 2018·Human Genome Variation·Angelo MinucciEttore Capoluongo
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
May 29, 2021·Scientific Reports·Kok-Siong Poon
Dec 10, 2021·Human Mutation·Qian LiangXuefeng Wang