Journal article

Combined genetic and splicing analysis of BRCA1 c.[594-2A > C; 641A > G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms

Miguel de la Hoya, Omar Soukarieh, Irene Lopez-Perolio, Ana Vega, Logan C Walker, Yvette van Ierland, Diana Baralle, Marta Santamarina, Vanessa Lattimore, Juul Wijnen, Philip Whiley, Ana Blanco, Michela Raponi, Jan Hauke, Barbara Wappenschmidt, Alexandra Becker, Thomas VO Hansen, Raquel Behar, Diether Niederacher, Norbert Arnold Show all

Human Molecular Genetics | OXFORD UNIV PRESS | Published : 2016

Abstract

A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10-8 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characteriz..

View full abstract

Grants

Awarded by Spanish Instituto de Salud Carlos III - European Regional Development FEDER Funds


Awarded by National Institute of Health


Awarded by NIH


Awarded by Cancer Council Queensland


Awarded by NHMRC


Awarded by German Cancer Aid


Awarded by Cancer Research UK


Awarded by National Cancer Institute


Awarded by Deutsche Krebshilfee.V.


Awarded by Federal Ministry of Education and Research (BMBF) Germany


Awarded by Specialized Program of Research Excellence (SPORE) in Breast Cancer


Awarded by Australian NHMRC


Awarded by CRUK


Awarded by European Community


Awarded by National Institutes of Health


Awarded by Post-Cancer GWAS initiative


Awarded by Department of Defence


Awarded by Cancer Research-UK


Awarded by NATIONAL CANCER INSTITUTE


Awarded by National Breast Cancer Foundation


Funding Acknowledgements

The research described was supported by Spanish Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [PI12/00539 and PI15/00059 to M.d.H., PI13/02030 to A.V.]; the French Ministry of Higher Education and Research [to O.S.]; the University of Otago, Mackenzie Charitable Foundation, Maria Lupton, and .Health Research Council of New Zealand [to L.W.]; UK Higher Education Funding Council Senior Fellowship Scheme, the University of Southampton [to D.B.]; Cancer research UK [to D.B., M.R.]; FamilienHede Nielsen Foundation fund [to T.V.O.H.]; Cancer Research-UK Senior Cancer Research Fellowship [to A.C.A.]; National Institute of Health [CA128978 and CA11616 to F.J.C.]; an NIH specialized program of research excellence in breast cancer to the Mayo Clinic [P50 CA116201 to F.J.C.]; and the US Breast Cancer Research Foundation [to F.J.C.]; translational grant from the French National Cancer Institute and Direction Generale de l'Offre des Soins (INCa-DGOS AAP/CFB/CI) and a grant from the French North-West Canceropole (CNO) [to A.M.]; The Cancer Council Queensland [APP1086286 to A.B.S.]; the NHMRC Senior Research Fellowship Scheme [ID 1061779 to A.B.S.]; NHMRC Project grant scheme [ID 1010719 to A.B.S.].Additional infrastructure support to consortium members is as follows: kConFab infrastructure has been supported by funding from the National Breast Cancer Foundation, National Health and Medical Research Council, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia [to kConFab, and the kConFab Clinical Follow-up study].The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC)The French consortium is supported by the French National Cancer Institute.EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990.BCFR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer (recently merged with Breast Cancer Campaign forming Breast Cancer Now) and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN).The BSUCH study was supported by the Dietmar-Hopp Foundation, the Helmholtz Society and the German Cancer Research Center (DKFZ).The CGPS was supported by the Chief Physician Johan Boserup and LiseBoserup Fund, the Danish Medical Research Council and Herlev HospitalKARBAC was supported financially through the regional agreement on medical training and clinical research (ALF) between Stockholm City Council and KarolinskaInstitutet, and from the Stockholm Cancer Foundation and the Swedish Cancer Society.The MARIE study was supported by the Deutsche Krebshilfee.V. [70-2892-BR I], the Hamburg Cancer Society, the German Cancer Research Center and the Federal Ministry of Education and Research (BMBF) Germany [01KH0402].MBCSG is supported by grants from the Italian Association for Cancer Research (AIRC) and by funds from the Italian citizens who allocated the 5/1000 share of their tax payment according to Italian laws in support of the Fondazione IRCCS IstitutoNazionaleTumori.The MCBCS was supported by the NIH grant CA128978 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201], the Breast Cancer Research Foundation and a generous gift from the David F. and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation.MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 251553 and 504711 and by infrastructure provided by Cancer Council Victoria.OFBCR was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.The pKARMA study was supported by Marit and Hans Rausings Initiative Against Breast Cancer, and the Swedish Medical Research Counsel.SEARCH was supported by grants CRUK A490/A11021, C490/A16561.Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund.CIMBA data management was supported by Cancer Research-UK grant C12292/A11174 and C1287/A10118.BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Communitys Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS).