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dc.contributor.authorColombo, M
dc.contributor.authorLòpez-Perolio, I
dc.contributor.authorMeeks, HD
dc.contributor.authorCaleca, L
dc.contributor.authorParsons, M
dc.contributor.authorLi, H;, De 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, M et al. [Incl Mannermaa, Arto; Kosma, Veli-Matti]
dc.date.accessioned2018-05-15T12:17:53Z
dc.date.available2018-05-15T12:17:53Z
dc.date.issued2018
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/6601
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.language.isoEN
dc.publisherWiley
dc.relation.ispartofseriesHUMAN MUTATION
dc.relation.urihttp://dx.doi.org/10.1002/humu.23411
dc.rightsCC BY http://creativecommons.org/licenses/by/4.0/
dc.titleThe BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity
dc.description.versionpublished version
dc.contributor.departmentSchool of Medicine / Clinical Medicine
uef.solecris.id52867628en
dc.type.publicationTieteelliset aikakauslehtiartikkelit
dc.rights.accessrights© Authors
dc.relation.doi10.1002/humu.23411
dc.description.reviewstatuspeerReviewed
dc.format.pagerange729-741
dc.relation.issn1059-7794
dc.relation.issue5
dc.relation.volume39
dc.rights.accesslevelopenAccess
dc.type.okmA1
uef.solecris.openaccessEi


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