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dc.contributor.authorHovland, Henrikke Nilsen
dc.contributor.authorMchaina, Eunice Kabanyana
dc.contributor.authorVetti, Hildegunn Høberg
dc.contributor.authorAriansen, Sarah Louise
dc.contributor.authorSjursen, Wenche
dc.contributor.authorVan Ghelue, Marijke
dc.contributor.authorHaukanes, Bjørn Ivar
dc.contributor.authorKnappskog, Per Morten
dc.contributor.authorAukrust, Ingvild
dc.contributor.authorBerge, Elisabet Ognedal
dc.date.accessioned2023-08-11T08:28:48Z
dc.date.available2023-08-11T08:28:48Z
dc.date.issued2023-01-19
dc.description.abstract: The BRCA1 protein is implicated in numerous important cellular processes to prevent genomic instability and tumorigenesis, and pathogenic germline variants predispose carriers to hereditary breast and ovarian cancer (HBOC). Most functional studies of missense variants in BRCA1 focus on variants located within the Really Interesting New Gene (RING), coiled-coil and BRCA1 C-terminal (BRCT) domains, and several missense variants in these regions have been shown to be pathogenic. However, the majority of these studies focus on domain specific assays, and have been performed using isolated protein domains and not the full-length BRCA1 protein. Furthermore, it has been suggested that BRCA1 missense variants located outside domains with known function are of no functional importance, and could be classified as (likely) benign. However, very little is known about the role of the regions outside the well-established domains of BRCA1, and only a few functional studies of missense variants located within these regions have been published. In this study, we have, therefore, functionally evaluated the effect of 14 rare BRCA1 missense variants considered to be of uncertain clinical significance, of which 13 are located outside the well-established domains and one within the RING domain. In order to investigate the hypothesis stating that most BRCA1 variants located outside the known protein domains are benign and of no functional importance, multiple protein assays including protein expression and stability, subcellular localisation and protein interactions have been performed, utilising the full-length protein to better mimic the native state of the protein. Two variants located outside the known domains (p.Met297Val and p.Asp1152Asn) and one variant within the RING domain (p.Leu52Phe) were found to make the BRCA1 protein more prone to proteasome-mediated degradation. In addition, two variants (p.Leu1439Phe and p.Gly890Arg) also located outside known domains were found to have reduced protein stability compared to the wild type protein. These findings indicate that variants located outside the RING, BRCT and coiled-coiled domains could also affect the BRCA1 protein function. For the nine remaining variants, no significant effects on BRCA1 protein functions were observed. Based on this, a reclassification of seven variants from VUS to likely benign could be suggested.en_US
dc.identifier.citationHovland, Mchaina, Vetti, Ariansen, Sjursen, Van Ghelue, Haukanes, Knappskog, Aukrust, Berge. Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions. Genes. 2023;14(2)en_US
dc.identifier.cristinIDFRIDAID 2133366
dc.identifier.doi10.3390/genes14020262
dc.identifier.issn2073-4425
dc.identifier.urihttps://hdl.handle.net/10037/29862
dc.language.isoengen_US
dc.publisherMDPIen_US
dc.relation.journalGenes
dc.rights.accessRightsopenAccessen_US
dc.rights.holderCopyright 2023 The Author(s)en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.rightsAttribution 4.0 International (CC BY 4.0)en_US
dc.titleFunctional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functionsen_US
dc.type.versionpublishedVersionen_US
dc.typeJournal articleen_US
dc.typeTidsskriftartikkelen_US
dc.typePeer revieweden_US


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Attribution 4.0 International (CC BY 4.0)
Except where otherwise noted, this item's license is described as Attribution 4.0 International (CC BY 4.0)