biostudies-literatureColombo MCancer Research UKCancer Council QueenslandBBMRIPink RibbonCancer Foundation Finland srNational Breast Cancer FoundationAssociazione Italiana per la Ricerca sul Cancrothe NHMRC Senior Research Fellowship SchemeMedical Research CouncilDutch Research Council (NWO)NHMRC Project grant schemeNational Institute for Health Research (NIHR)NCI NIH HHSSpanish Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER FundsTranscanWellcome TrustKWF Kankerbestrijding729-741https://www.ebi.ac.uk/biostudies/studies/S-EPMC5947288biostudies-literatureUnknown39(5)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^-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.Human mutationThe BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.PMC59472882014-187.WO76110005NWO 184.021.007/CP46P30 CA008748184.021.007NKI1998-185403/DHCS/03/G121/5116459MC_PC_14105NKI2007-37561701201267720861N°15547 to P.R.11013516563130168NKI2004-308NWO 91109024P50 CA116201203477/Z/16/ZR01 CA192393170159P30 CA016058IF-17-002150147JTC 2012IF-12-06Flyger HDork TSouthey MCHebon SCross SSLubinski JBeeghly-Fadel ALe Marchand LGoldgar DEMcGuffog LLopez-Perolio IkConFab/AOCS InvestigatorsBurwinkel BEaston DFSchmidt AYFletcher ODe Vecchi GParsons MTMeeks HDZheng WHall PPeto JSchmutzler RKCaleca LFigueroa JBrenner HNeuhausen SLTruong TWinqvist RColombo MHenderson AHogervorst FBLSide LEBrauch HBenitez JBojesen SEBogdanova NVBonanni BEmbrace SNiederacher Dvan Asperen CJPeterlongo PCox AHauke JSpurdle ABLindblom AJung AManoukian SMontagna MLambrechts DBoeckx BConroy DMDunning AMKosma VMGarcia-Closas MGarcia EBGToland AEFoglia CAndrulis ILAntoniou ACGuenel Pvan den Ouweland AMWBehar RWang QCouch FJChenevix-Trench GAittomaki Kvan Rensburg EJLi HBolla MKSchoemaker MJMilne RLChang-Claude JFasching PATeo SHGabrielson MSchmidt MKNevanlinna HMichailidou Kvan der Kolk LEArndt VEriksson MTudini EVaresco LIzatt LAnton-Culver HSwerdlow AMiao HPylkas KTomlinson IHollestelle AYannoukakos DRadice PMondini PBeckmann MWDevilee PGiles GGHaiman CASchneeweiss AGonzalez-Neira AOffitt KCzene KMargolin SDennis JSawyer EJHoya MOlson JEWappenschmidt BHopper JLSee MHHamann UJakubowska AHartman MMannermaa AMeindl AfalseThe BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.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^-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.2018-01-01T00:00:00Z2018 May2024-11-11T22:09:30.497Z2019-03-26T23:37:45ZS-EPMC59472882946099510.1002/humu.23411