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dc.contributor.authorDominguez-Valentin, Mev
dc.contributor.authorEvans, D. G R
dc.contributor.authorNakken, Sigve
dc.contributor.authorTubeuf, Hélène
dc.contributor.authorVodak, Daniel
dc.contributor.authorEkstrøm, Per O
dc.contributor.authorNissen, Anke M
dc.contributor.authorMorak, Monika
dc.contributor.authorHolinski-Feder, Elke
dc.contributor.authorMartins, Alexandra
dc.contributor.authorMøller, Pål
dc.contributor.authorHovig, Eivind
dc.date.accessioned2018-01-16T06:03:34Z
dc.date.available2018-01-16T06:03:34Z
dc.date.issued2018
dc.identifier.citationHereditary Cancer in Clinical Practice. 2018 Jan 15;16(1):4
dc.identifier.urihttp://hdl.handle.net/10852/59628
dc.description.abstractBackground In kindreds carrying path_BRCA1/2 variants, some women in these families will develop cancer despite testing negative for the family’s pathogenic variant. These families may have additional genetic variants, which not only may increase the susceptibility of the families’ path_BRCA1/2, but also be capable of causing cancer in the absence of the path_BRCA1/2 variants. We aimed to identify novel genetic variants in prospectively detected breast cancer (BC) or gynecological cancer cases tested negative for their families’ pathogenic BRCA1/2 variant (path_BRCA1 or path_BRCA2). Methods Women with BC or gynecological cancer who had tested negative for path_BRCA1 or path_BRCA2 variants were included. Forty-four cancer susceptibility genes were screened for genetic variation through a targeted amplicon-based sequencing assay. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the ones most likely affecting pre-mRNA splicing were experimentally analyzed in a minigene assay. Results We identified 48 women who were tested negative for their family’s path_BRCA1 (n = 13) or path_BRCA2 (n = 35) variants. Pathogenic variants in the ATM, BRCA2, MSH6 and MUTYH genes were found in 10% (5/48) of the cases, of whom 15% (2/13) were from path_BRCA1 and 9% (3/35) from path_BRCA2 families. Out of the 26 unique VUS, 3 (12%) were predicted to affect RNA splicing (APC c.721G > A, MAP3K1 c.764A > G and MSH2 c.815C > T). However, by using a minigene, assay we here show that APC c.721G > A does not cause a splicing defect, similarly to what has been recently reported for the MAP3K1 c.764A > G. The MSH2 c.815C > T was previously described as causing partial exon skipping and it was identified in this work together with the path_BRCA2 c.9382C > T (p.R3128X). Conclusion All women in breast or breast/ovarian cancer kindreds would benefit from being offered genetic testing irrespective of which causative genetic variants have been demonstrated in their relatives.
dc.language.isoeng
dc.rightsThe Author(s); licensee BioMed Central Ltd.
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.titleGenetic variants of prospectively demonstrated phenocopies in BRCA1/2 kindreds
dc.typeJournal article
dc.date.updated2018-01-16T06:03:37Z
dc.creator.authorDominguez-Valentin, Mev
dc.creator.authorEvans, D. G R
dc.creator.authorNakken, Sigve
dc.creator.authorTubeuf, Hélène
dc.creator.authorVodak, Daniel
dc.creator.authorEkstrøm, Per O
dc.creator.authorNissen, Anke M
dc.creator.authorMorak, Monika
dc.creator.authorHolinski-Feder, Elke
dc.creator.authorMartins, Alexandra
dc.creator.authorMøller, Pål
dc.creator.authorHovig, Eivind
dc.identifier.cristin1598932
dc.identifier.doihttp://dx.doi.org/10.1186/s13053-018-0086-0
dc.identifier.urnURN:NBN:no-62307
dc.type.documentTidsskriftartikkel
dc.type.peerreviewedPeer reviewed
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/59628/1/13053_2018_Article_86.pdf
dc.type.versionPublishedVersion
cristin.articleid4


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