ArticleHuman mutation2018
The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.
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Article in Human mutation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11citing papers in PubMed
2.9field-weighted citation impact, top 9% of its field
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Who cites it
11 citing papers in PubMed, 20 citations in OpenAlex.
- The PARP1 selective inhibitor saruparib (AZD5305) elicits potent and durable antitumor activity in patient-derived BRCA1/2-associated cancer models.Genome medicine · 2024Article
- A novelFrontiers in oncology · 2023Article
- Clinical, splicing, and functional analysis to classify BRCA2 exon 3 variants: Application of a points-based ACMG/AMP approach.Human mutation · 2022Article
- Interpretation of BRCA2 Splicing Variants: A Case Series of Challenging Variant Interpretations and the Importance of Functional RNA Analysis.Familial cancer · 2022Article
- Spectrum of splicing variants in disease genes and the ability of RNA analysis to reduce uncertainty in clinical interpretation.American journal of human genetics · 2021Article
- Splicing Outcomes of 5' Splice Site GT>GC Variants That Generate Wild-Type Transcripts Differ Significantly Between Full-Length and Minigene Splicing Assays.Frontiers in genetics · 2021Article
- Calibration of Pathogenicity Due to Variant-Induced Leaky Splicing Defects by UsingCancer research · 2020Article
- Article
- The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.Human mutation · 2018Article
- Quantitative Analysis ofFrontiers in oncology · 2018Article
- Retraction Note to: TheHereditary cancer in clinical practice · 2018Article
Corrections and comments
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Authors and funding
115 authors at 20 institutions in 20 countries.
Mara ColomboUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.ORCID 0000-0001-5465-354X
Irene Lòpez-PerolioMolecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
Huong D MeeksHuntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Laura CalecaUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
Michael T ParsonsDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Hongyan LiHuntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Giovanna De VecchiUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
Emma TudiniDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Claudia FogliaUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
Patrizia MondiniUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
Siranoush ManoukianUnit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
Raquel BeharMolecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
Encarna B Gómez GarciaDepartment of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands.
Alfons MeindlDepartment of Obstetrics and Gynecology, University Hospital, LMU Munich, Germany.
Marco MontagnaImmunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
Dieter NiederacherDepartment of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Duesseldorf, Germany.
Ane Y SchmidtCenter for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Liliana VarescoHereditary Cancer Unit, IRCCS AOU San Martino -IST, Genova, Italy.
Barbara WappenschmidtCenter for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
Manjeet K BollaCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Joe DennisCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Kyriaki MichailidouCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Qin WangCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Kristiina AittomäkiDepartment of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Irene L AndrulisFred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario.
Hoda Anton-CulverDepartment of Epidemiology, University of California Irvine, Irvine, California.
Volker ArndtDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Matthias W BeckmannDepartment of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
Alicia Beeghly-FadelDivision of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Javier BenitezHuman Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
Bram BoeckxVIB Center for Cancer Biology, VIB, Leuven, Belgium.
Natalia V BogdanovaDepartment of Radiation Oncology, Hannover Medical School, Hannover, Germany.
Stig E BojesenCopenhagen General Population Study, Herlevand Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Bernardo BonanniDivision of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
Hiltrud BrauchDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
Hermann BrennerDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Barbara BurwinkelDepartment of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
Jenny Chang-ClaudeDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Don M ConroyCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Fergus J CouchDepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, New York.
Angela CoxSheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
Simon S CrossAcademic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
Kamila CzeneDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Peter DevileeDepartment of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Thilo DörkGynaecology Research Unit, Hannover Medical School, Hannover, Germany.
Mikael ErikssonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Peter A FaschingDepartment of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany.
Jonine FigueroaUsher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh, UK.
Olivia FletcherThe Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
Henrik FlygerDepartment of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
Marike GabrielsonDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Montserrat García-ClosasDivision of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
Graham G GilesCancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.
Anna González-NeiraHuman Cancer Genetics Program, Spanish National Cancer Research Centre, Madrid, Spain.
Pascal GuénelCancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
Christopher A HaimanDepartment of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
Per HallDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Ute HamannMolecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.
Mikael HartmanSaw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
Jan HaukeCenter for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
Antoinette HollestelleDepartment of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
John L HopperCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global health, The University of Melbourne, Melbourne, Australia.
Anna JakubowskaDepartment of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Audrey JungDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Veli-Matti KosmaTranslational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
Diether LambrechtsVIB Center for Cancer Biology, VIB, Leuven, Belgium.
Loid Le MarchandEpidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
Annika LindblomDepartment of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Jan LubinskiDepartment of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
Arto MannermaaTranslational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
Sara MargolinDepartment of Clinical Science and Education Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
Hui MiaoSaw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
Roger L MilneCancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia.
Susan L NeuhausenDepartment of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
Heli NevanlinnaDepartment of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Janet E OlsonDepartment of Health Sciences Research, Mayo Clinic, Rochester, New York.
Paolo PeterlongoIFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.
Julian PetoDepartment of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
Katri PylkäsLaboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
Elinor J SawyerResearch Oncology, Guy's Hospital, King's College London, London, UK.
Marjanka K SchmidtDivision of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Rita K SchmutzlerCenter for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany.
Andreas SchneeweissDepartment of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany.
Minouk J SchoemakerDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Mee Hoong SeeBreast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
Melissa C SoutheyDepartment of Pathology, The University of Melbourne, Melbourne, Australia.
Anthony SwerdlowDivision of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Soo H TeoBreast Cancer Research Unit, Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia.
Amanda E TolandDepartment of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Ian TomlinsonWellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.
Thérèse TruongCancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif, France.
Christi J van AsperenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Ans M W van den OuwelandDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Lizet E van der KolkFamily Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
Robert WinqvistLaboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
Drakoulis YannoukakosMolecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece.
Wei ZhengDivision of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
kConFab/AOCS InvestigatorsPeter MacCallum Cancer Center, Melbourne, Australia.
Alison M DunningCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
Douglas F EastonCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Alex HendersonInstitute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK.
Frans B L HogervorstFamily Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
Louise IzattClinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
Kenneth OffittClinical Genetics Research Laboratory, Dept. of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York.
Lucy E SideWessex Clinical Genetics Service, Mailpoint 627, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA.
Elizabeth J van RensburgCancer Genetics Laboratory, Department of Genetics, University of Pretoria, Pretoria, South Africa.
Study EmbraceCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
Study HebonThe Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating center: Netherlands Cancer Institute, Amsterdam, The Netherlands.
Lesley McGuffogCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Antonis C AntoniouCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Georgia Chenevix-TrenchDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
Amanda B SpurdleDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
David E GoldgarHuntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Miguel de la HoyaMolecular Oncology Laboratory CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
Paolo RadiceUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale dei Tumori (INT), Milan, Italy.
University of Cambridge · GBFondazione IRCCS Istituto Nazionale dei Tumori · ITGerman Cancer Research Center · DEKarolinska Institutet · SEQIMR Berghofer Medical Research Institute · AUThe University of Melbourne · AUInstitute of Cancer Research · GBInstituto de Investigación Sanitaria del Hospital Clínico San Carlos · ESUniversity of Utah · USInserm · FRLeiden University Medical Center · NLMedizinische Hochschule Hannover · DEMemorial Sloan Kettering Cancer Center · USNational Cancer Institute · USNational University of Singapore · SGNordLab · FIPomeranian Medical University · PLSpanish National Cancer Research Centre · ESThe Netherlands Cancer Institute · NLUniversity Malaya Medical Centre · MY
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Nicholas D Socci · 1985 to 2026
$347.4MTranslational Therapeutics Research Program (TT)P30CA016058 · NCI · OHIO STATE UNIVERSITY · PI Tasleem J Padamsee · 1985 to 2026
$132.3MHormone-Related CancersZIACP010126 · NCI · DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS · PI GIERACH, GRETCHEN · 2009 to 2025
$103.5MThe Role of CHFR in Tumorigenesis and Paclitaxel-Sensitivity in Breast CancerP50CA116201 · NCI · MAYO CLINIC ROCHESTER · PI PETER C LUCAS · 2005 to 2026
$49.9MRisk and penetrance of mutations from breast cancer testing panels.R01CA192393 · NCI · MAYO CLINIC ROCHESTER · PI COUCH, FERGUS JOSEPH, NATHANSON, KATHERINE L. · 2014 to 2018
$6.3MCancer Research UK 12677Cancer Research UK 16459Cancer Research UK 16563Cancer Research UK 16565Cancer Research UK 17523Cancer Research UK 20861Cancer Research UK 23382Medical Research Council MC_PC_14105NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA016058NCI NIH HHS P50 CA116201NCI NIH HHS R01 CA192393Wellcome Trust 203477/Z/16/Z
Abstract
Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10
Indexed as
Genetic VariationModels, GeneticBase SequenceBRCA2 ProteinCalibrationCell LineExonsFemaleGenetic Predisposition to DiseaseHumansMitomycinRNA, MessengerRNA SplicingBRCA2 ProteinBRCA2 protein, humanMitomycinRNA, MessengerBRCA2digital PCRmultifactorial likelihood analysisquantitative real-time PCRspliceogenic variants
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