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dc.contributor.authorColombo, M
dc.contributor.authorLòpez-Perolio, I
dc.contributor.authorMeeks, HD
dc.contributor.authorCaleca, L
dc.contributor.authorParsons, MT
dc.contributor.authorLi, H
dc.contributor.authorDe Vecchi, G
dc.contributor.authorTudini, E
dc.contributor.authorFoglia, C
dc.contributor.authorMondini, P
dc.contributor.authorManoukian, S
dc.contributor.authorBehar, R
dc.contributor.authorGarcia, EBG
dc.contributor.authorMeindl, A
dc.contributor.authorMontagna, M
dc.contributor.authorNiederacher, D
dc.contributor.authorSchmidt, AY
dc.contributor.authorVaresco, L
dc.contributor.authorWappenschmidt, B
dc.contributor.authorBolla, MK
dc.contributor.authorDennis, J
dc.contributor.authorMichailidou, K
dc.contributor.authorWang, Q
dc.contributor.authorAittomäki, K
dc.contributor.authorAndrulis, IL
dc.contributor.authorAnton-Culver, H
dc.contributor.authorArndt, V
dc.contributor.authorBeckmann, MW
dc.contributor.authorBeeghly-Fadel, A
dc.contributor.authorBenitez, J
dc.contributor.authorBoeckx, B
dc.contributor.authorBogdanova, NV
dc.contributor.authorBojesen, SE
dc.contributor.authorBonanni, B
dc.contributor.authorBrauch, H
dc.contributor.authorBrenner, H
dc.contributor.authorBurwinkel, B
dc.contributor.authorChang-Claude, J
dc.contributor.authorConroy, DM
dc.contributor.authorCouch, FJ
dc.contributor.authorCox, A
dc.contributor.authorCross, SS
dc.contributor.authorCzene, K
dc.contributor.authorDevilee, P
dc.contributor.authorDörk, T
dc.contributor.authorEriksson, M
dc.contributor.authorFasching, PA
dc.contributor.authorFigueroa, J
dc.contributor.authorFletcher, O
dc.contributor.authorFlyger, H
dc.contributor.authorGabrielson, M
dc.contributor.authorGarcía-Closas, M
dc.contributor.authorGiles, GG
dc.contributor.authorGonzález-Neira, A
dc.contributor.authorGuénel, P
dc.contributor.authorHaiman, CA
dc.contributor.authorHall, P
dc.contributor.authorHamann, U
dc.contributor.authorHartman, M
dc.contributor.authorHauke, J
dc.contributor.authorHollestelle, A
dc.contributor.authorHopper, JL
dc.contributor.authorJakubowska, A
dc.contributor.authorJung, A
dc.contributor.authorKosma, V-M
dc.contributor.authorLambrechts, D
dc.contributor.authorLe Marchand, L
dc.contributor.authorLindblom, A
dc.contributor.authorLubinski, J
dc.contributor.authorMannermaa, A
dc.contributor.authorMargolin, S
dc.contributor.authorMiao, H
dc.contributor.authorMilne, RL
dc.contributor.authorNeuhausen, SL
dc.contributor.authorNevanlinna, H
dc.contributor.authorOlson, JE
dc.contributor.authorPeterlongo, P
dc.contributor.authorPeto, J
dc.contributor.authorPylkäs, K
dc.contributor.authorSawyer, EJ
dc.contributor.authorSchmidt, MK
dc.contributor.authorSchmutzler, RK
dc.contributor.authorSchneeweiss, A
dc.contributor.authorSchoemaker, MJ
dc.contributor.authorSee, MH
dc.contributor.authorSouthey, MC
dc.contributor.authorSwerdlow, A
dc.contributor.authorTeo, SH
dc.contributor.authorToland, AE
dc.contributor.authorTomlinson, I
dc.contributor.authorTruong, T
dc.contributor.authorvan Asperen, CJ
dc.contributor.authorvan den Ouweland, AMW
dc.contributor.authorvan der Kolk, LE
dc.contributor.authorWinqvist, R
dc.contributor.authorYannoukakos, D
dc.contributor.authorZheng, W
dc.contributor.authorkConFab/AOCS Investigators,
dc.contributor.authorDunning, AM
dc.contributor.authorEaston, DF
dc.contributor.authorHenderson, A
dc.contributor.authorHogervorst, FBL
dc.contributor.authorIzatt, L
dc.contributor.authorOffitt, K
dc.contributor.authorSide, LE
dc.contributor.authorvan Rensburg, EJ
dc.contributor.authorEmbrace, S
dc.contributor.authorHebon, S
dc.contributor.authorMcGuffog, L
dc.contributor.authorAntoniou, AC
dc.contributor.authorChenevix-Trench, G
dc.contributor.authorSpurdle, AB
dc.contributor.authorGoldgar, DE
dc.contributor.authorHoya, MDL
dc.contributor.authorRadice, P
dc.date.accessioned2019-01-25T09:25:06Z
dc.date.issued2018-05-01
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000433600000012&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=d4b848928d1c3e5c86d298abb68475f9
dc.identifier.citationHUMAN MUTATION, 2018, 39 (5), pp. 729 - 741
dc.identifier.issn1059-7794
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3020
dc.identifier.eissn1098-1004
dc.identifier.doi10.1002/humu.23411
dc.description.abstractAlthough 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.
dc.format.extent729 - 741
dc.languageeng
dc.language.isoeng
dc.publisherWILEY
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectBRCA2
dc.subjectdigital PCR
dc.subjectmultifactorial likelihood analysis
dc.subjectquantitative real-time PCR
dc.subjectspliceogenic variants
dc.titleThe BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.
dc.typeJournal Article
dcterms.dateAccepted2018-02-10
rioxxterms.versionofrecord10.1002/humu.23411
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-05
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfHUMAN MUTATION
pubs.issue5
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Aetiological Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genetic Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Aetiological Epidemiology
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Aetiological Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Functional Genetic Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Genetics and Epidemiology/Aetiological Epidemiology
pubs.publication-statusPublished
pubs.volume39
pubs.embargo.termsNot known
icr.researchteamFunctional Genetic Epidemiology
icr.researchteamAetiological Epidemiology
dc.contributor.icrauthorFletcher, Olivia
dc.contributor.icrauthorSchoemaker, Minouk
dc.contributor.icrauthorSwerdlow, Anthony


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