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Genetic screening of mainly patients with breast and ovarian cancer has identified numerous\n                      <jats:italic>BRCA1<\/jats:italic>\n                      \/\n                      <jats:italic>BRCA2<\/jats:italic>\n                      variants of uncertain significance (VUS) that remain unclassified owing to a lack of pedigrees and functional data.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      Here, we used CRISPR-Select \u2014 a technology that exploits unique inbuilt controls at the endogenous locus \u2014 to assess 54 rare ClinVar VUS located in the PALB2-binding domain of\n                      <jats:italic>BRCA2<\/jats:italic>\n                      . Variant deleteriousness was examined in the absence and presence of PARPi, cisplatin, or mitomycin C.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Marked functional deficiency was observed for variants in the exon 2 donor splice region (A22 = c.66A&gt;C, A22 = c.66A&gt;G, A22 = c.66A&gt;T, and D23H) and Trp31 aa (W31G, W31L, and W31C), both critical for\n                      <jats:italic>BRCA2<\/jats:italic>\n                      function. Moreover, T10K and G25R resulted in an intermediate phenotype, suggesting these variants are hypomorphic in nature. Combining our functional results with the latest ClinGen\n                      <jats:italic>BRCA1\/2<\/jats:italic>\n                      Variant Curation Expert Panel recommendations, we classified 49 of the 54 VUS as either likely benign (\n                      <jats:italic>n<\/jats:italic>\n                      = 45) or likely pathogenic (\n                      <jats:italic>n<\/jats:italic>\n                      = 4).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Therefore, CRISPR-Select is an important tool for efficient variant clinical classification. Application of this technology in the future will ultimately improve patient care.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>Danish Cancer Society, Novo Nordisk Foundation, Sygeforsikring Danmark, B\u00f8rnecancerfonden, Neye-Fonden, Roche, Novartis, Pfizer, AstraZeneca, MSD, and Daiichi Sankyo Europe GmbH.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci181879","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T12:00:37Z","timestamp":1744718437000},"source":"Crossref","is-referenced-by-count":5,"title":["Precision screening facilitates clinical classification of BRCA2-PALB2 binding variants with benign and pathogenic functional effects"],"prefix":"10.1172","volume":"135","author":[{"given":"Muthiah","family":"Bose","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manika Indrajit","family":"Singh","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morten","family":"Fr\u00f6din","sequence":"additional","affiliation":[{"name":"Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bent","family":"Ejlertsen","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark."},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus S.","family":"S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Biotech Research and Innovation Center, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Rossing","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark."},{"name":"Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.7112"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.02112"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2018.6228"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-018-0052-2"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20880"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1153"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-021-06441-y"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.02225"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20897"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21627"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21628"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-020-01554-6"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-2081"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-22-0203"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds222"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16141-8"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0461-z"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2024.07.013"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01201-1"},{"key":"B21","doi-asserted-by":"crossref","unstructured":"Huang H, et al. 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