{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T23:47:28Z","timestamp":1768002448209,"version":"3.49.0"},"reference-count":62,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004257","name":"Western Norway Regional Health Authority and the Western Norway Familial Cancer Center","doi-asserted-by":"publisher","award":["F-10199\/4800001941"],"award-info":[{"award-number":["F-10199\/4800001941"]}],"id":[{"id":"10.13039\/501100004257","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes14020262","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T05:50:20Z","timestamp":1674107420000},"page":"262","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Functional Analyses of Rare Germline Missense BRCA1 Variants Located within and outside Protein Domains with Known Functions"],"prefix":"10.3390","volume":"14","author":[{"given":"Henrikke Nilsen","family":"Hovland","sequence":"first","affiliation":[{"name":"Western Norway Familial Cancer Center, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Department of Clinical Science, University of Bergen, 5021 Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eunice Kabanyana","family":"Mchaina","sequence":"additional","affiliation":[{"name":"Western Norway Familial Cancer Center, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9876-576X","authenticated-orcid":false,"given":"Hildegunn","family":"H\u00f8berg-Vetti","sequence":"additional","affiliation":[{"name":"Western Norway Familial Cancer Center, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Faculty of Health Studies, VID Specialized University, 5009 Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah Louise","family":"Ariansen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenche","family":"Sjursen","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, St. Olavs University Hospital, 7006 Trondheim, Norway"},{"name":"Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marijke","family":"Van Ghelue","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, University Hospital of North Norway, 9038 Troms\u00f8, Norway"},{"name":"Department of Clinical Science, UiT The Arctic University of Norway, 9019 Troms\u00f8, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1559-3366","authenticated-orcid":false,"given":"Bj\u00f8rn Ivar","family":"Haukanes","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per Morten","family":"Knappskog","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Department of Clinical Science, University of Bergen, 5021 Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingvild","family":"Aukrust","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Department of Clinical Science, University of Bergen, 5021 Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabet","family":"Ognedal","sequence":"additional","affiliation":[{"name":"Western Norway Familial Cancer Center, Haukeland University Hospital, 5021 Bergen, Norway"},{"name":"Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1086\/375033","article-title":"Average Risks of Breast and Ovarian Cancer Associated with BRCA1 or BRCA2 Mutations Detected in Case Series Unselected for Family History: A Combined Analysis of 22 Studies","volume":"72","author":"Antoniou","year":"2003","journal-title":"Am. 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