دورية أكاديمية
Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.
| العنوان: | Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach. |
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| المؤلفون: | Thomassen M; Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark., Mesman RLS; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands., Hansen TVO; Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Menendez M; Hereditary Cancer Program, Catalan Institute of Oncology, ONCOBELL-IDIBELL-IDTP, CIBERONC, Hospitalet de Llobregat, Spain., Rossing M; Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Esteban-Sánchez A; Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain., Tudini E; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Törngren T; Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Parsons MT; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Pedersen IS; Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.; Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark., Teo SH; Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.; Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Kruse TA; Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark., Møller P; Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway., Borg Å; Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Jensen UB; Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark., Christensen LL; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark., Singer CF; Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Muhr D; Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria., Santamarina M; Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.; Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain., Brandao R; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands., Andresen BS; Department of Biochemistry and Molecular Biology and the Villum Center for Bioanalytical Sciences, University of Southern Denmark, Odense, Denmark., Feng BJ; Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA., Canson D; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Richardson ME; Ambry Genetics, Aliso Viejo, California, USA., Karam R; Ambry Genetics, Aliso Viejo, California, USA., Pesaran T; Ambry Genetics, Aliso Viejo, California, USA., LaDuca H; Ambry Genetics, Aliso Viejo, California, USA., Conner BR; Ambry Genetics, Aliso Viejo, California, USA., Abualkheir N; Ambry Genetics, Aliso Viejo, California, USA., Hoang L; Ambry Genetics, Aliso Viejo, California, USA., Calléja FMGR; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands., Andrews L; Hereditary Cancer Clinic, Nelune Comprehensive Cancer Care Centre, Sydney, New South Wales, Australia., James PA; Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia., Bunyan D; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK., Hamblett A; Middlesex Health Shoreline Cancer Center, Westbrook, Connecticut, USA., Radice P; Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy., Goldgar DE; Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, USA., Walker LC; Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand., Engel C; Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany., Claes KBM; Centre for Medical Genetics, Ghent University, Gent, Belgium., Macháčková E; Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic., Baralle D; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK., Viel A; Division of Functional Onco-genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy., Wappenschmidt B; Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.; Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany., Lazaro C; Hereditary Cancer Program, Catalan Institute of Oncology, ONCOBELL-IDIBELL-IDTP, CIBERONC, Hospitalet de Llobregat, Spain., Vega A; Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.; Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.; Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain., Vreeswijk MPG; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands., de la Hoya M; Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain., Spurdle AB; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| مؤلفون مشاركون: | ENIGMA Consortium; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| المصدر: | Human mutation [Hum Mutat] 2022 Dec; Vol. 43 (12), pp. 1921-1944. Date of Electronic Publication: 2022 Oct 23. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-Liss Country of Publication: United States NLM ID: 9215429 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-1004 (Electronic) Linking ISSN: 10597794 NLM ISO Abbreviation: Hum Mutat Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: New York : Wiley-Liss, c1992- |
| مواضيع طبية MeSH: | Genes, BRCA2* , RNA Splice Sites*, Animals ; Humans ; Mice ; Alternative Splicing ; BRCA2 Protein/genetics ; BRCA2 Protein/metabolism ; RNA Splicing ; RNA, Messenger/genetics ; RNA, Messenger/metabolism |
| مستخلص: | Skipping of BRCA2 exon 3 (∆E3) is a naturally occurring splicing event, complicating clinical classification of variants that may alter ∆E3 expression. This study used multiple evidence types to assess pathogenicity of 85 variants in/near BRCA2 exon 3. Bioinformatically predicted spliceogenic variants underwent mRNA splicing analysis using minigenes and/or patient samples. ∆E3 was measured using quantitative analysis. A mouse embryonic stem cell (mESC) based assay was used to determine the impact of 18 variants on mRNA splicing and protein function. For each variant, population frequency, bioinformatic predictions, clinical data, and existing mRNA splicing and functional results were collated. Variant class was assigned using a gene-specific adaptation of ACMG/AMP guidelines, following a recently proposed points-based system. mRNA and mESC analysis combined identified six variants with transcript and/or functional profiles interpreted as loss of function. Cryptic splice site use for acceptor site variants generated a transcript encoding a shorter protein that retains activity. Overall, 69/85 (81%) variants were classified using the points-based approach. Our analysis shows the value of applying gene-specific ACMG/AMP guidelines using a points-based approach and highlights the consideration of cryptic splice site usage to appropriately assign PVS1 code strength. (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.) |
| References: | Genet Med. 2020 Aug;22(8):1355-1365. (PMID: 32398771) Hum Mol Genet. 2016 Jun 1;25(11):2256-2268. (PMID: 27008870) Hum Mutat. 2014 Jan;35(1):53-7. (PMID: 24123850) Genet Med. 2020 Apr;22(4):701-708. (PMID: 31853058) Cancers (Basel). 2021 Jun 25;13(13):. (PMID: 34202044) Hum Mutat. 2020 Oct;41(10):1734-1737. (PMID: 32720330) Clin Cancer Res. 2010 Mar 15;16(6):1957-67. (PMID: 20215541) Hum Mutat. 2012 Jan;33(1):2-7. (PMID: 21990146) Nat Genet. 1997 Jan;15(1):103-5. (PMID: 8988179) Nat Commun. 2020 May 22;11(1):2573. (PMID: 32444794) Hum Mutat. 2008 Nov;29(11):1265-72. (PMID: 18951437) Mol Cell. 2006 Jun 23;22(6):719-729. (PMID: 16793542) Genet Med. 2020 May;22(5):825-830. (PMID: 31911673) Bioinformatics. 2019 Jul 1;35(13):2315-2317. (PMID: 30475984) Oncotarget. 2018 Apr 3;9(25):17334-17348. (PMID: 29707112) J Comput Biol. 2004;11(2-3):377-94. (PMID: 15285897) PLoS Genet. 2016 Aug 04;12(8):e1006236. (PMID: 27490902) Hum Mutat. 2020 Oct;41(10):1705-1721. (PMID: 32623769) N Engl J Med. 2021 Feb 4;384(5):428-439. (PMID: 33471991) Breast Cancer Res. 2014 Dec 23;16(6):3419. (PMID: 25857409) Am J Hum Genet. 2007 Nov;81(5):873-83. (PMID: 17924331) Hum Mutat. 2008 Nov;29(11):1342-54. (PMID: 18951461) Genet Med. 2018 Sep;20(9):1054-1060. (PMID: 29300386) Hum Mol Genet. 2012 Sep 15;21(18):3993-4006. (PMID: 22678057) Mol Cell. 2020 Jun 4;78(5):951-959.e6. (PMID: 32359443) Breast Cancer Res Treat. 2009 Mar;114(1):31-8. (PMID: 18363094) Hum Mutat. 2018 Nov;39(11):1517-1524. (PMID: 30192042) Cell. 2019 Jan 24;176(3):535-548.e24. (PMID: 30661751) Proc Natl Acad Sci U S A. 2009 Apr 28;106(17):7155-60. (PMID: 19369211) Genet Med. 2015 May;17(5):405-24. (PMID: 25741868) Hum Mutat. 2022 Dec;43(12):1921-1944. (PMID: 35979650) Hum Mutat. 2018 May;39(5):729-741. (PMID: 29460995) Cancer Res. 1998 Apr 1;58(7):1372-5. (PMID: 9537232) J Pathol. 2022 Mar;256(3):321-334. (PMID: 34846068) Genet Med. 2019 Feb;21(2):293-302. (PMID: 29988080) Nat Rev Genet. 2002 Apr;3(4):285-98. (PMID: 11967553) J Clin Oncol. 2007 Nov 1;25(31):5035-6; author reply 5036-8. (PMID: 17971607) Front Oncol. 2018 Jul 27;8:286. (PMID: 30101128) Fam Cancer. 2022 Jan;21(1):7-19. (PMID: 33469799) NPJ Precis Oncol. 2020 Feb 24;4:4. (PMID: 32133419) J Med Genet. 2016 Aug;53(8):548-58. (PMID: 27060066) J Pathol. 2019 Aug;248(4):409-420. (PMID: 30883759) EMBO Rep. 2009 Sep;10(9):990-6. (PMID: 19609323) Am J Hum Genet. 2004 Oct;75(4):535-44. (PMID: 15290653) Am J Hum Genet. 2018 Feb 1;102(2):233-248. (PMID: 29394989) Breast Cancer Res Treat. 2012 Apr;132(3):1009-23. (PMID: 21769658) Hum Mutat. 2018 Sep;39(9):1155-1160. (PMID: 29969168) Hum Mutat. 2019 Sep;40(9):1557-1578. (PMID: 31131967) Cancer Res. 2020 Sep 1;80(17):3593-3605. (PMID: 32641407) BMC Cancer. 2009 Jun 29;9:211. (PMID: 19563646) Am J Hum Genet. 2003 Sep;73(3):652-5. (PMID: 12900794) Gastroenterology. 2019 May;156(6):1924-1925.e4. (PMID: 30710526) |
| معلومات مُعتمدة: | 203477/Z/16/Z United Kingdom WT_ Wellcome Trust; RP-2016-07- 011 United Kingdom DH_ Department of Health |
| فهرسة مساهمة: | Keywords: ACMG/AMP classification; BRCA2; dPCR; functional analysis; quantitation; splicing |
| المشرفين على المادة: | 0 (BRCA2 Protein) 0 (BRCA2 protein, human) 0 (RNA Splice Sites) 0 (RNA, Messenger) |
| تواريخ الأحداث: | Date Created: 20220818 Date Completed: 20221227 Latest Revision: 20240320 |
| رمز التحديث: | 20240320 |
| مُعرف محوري في PubMed: | PMC10946542 |
| DOI: | 10.1002/humu.24449 |
| PMID: | 35979650 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-1004 |
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| DOI: | 10.1002/humu.24449 |