{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T11:15:06Z","timestamp":1792581306744,"version":"4.5.0"},"reference-count":36,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Sol Goldman Pancreatic Cancer Research Center","award":["Pilot Grant"],"award-info":[{"award-number":["Pilot Grant"]}]},{"name":"The Rolfe Pancreatic Cancer Foundation"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 CA622924"],"award-info":[{"award-number":["P50 CA622924"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Japanese Society of Gastroenterology"},{"DOI":"10.13039\/501100001691","name":"The Japan Society for Promotion of Science","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Joseph C Monastra Foundation"},{"name":"The Geral O Mann Foundation"},{"name":"Art Creates Cures Foundation"},{"name":"Susan Wojcicki and Denis Troper"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["S10 OD026859"],"award-info":[{"award-number":["S10 OD026859"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2022,1,6]]},"abstract":"<jats:p>\n                    Pathogenic germline\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    variants are associated with an increased risk of pancreatic ductal adenocarcinoma (PDAC).\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    variants of uncertain significance (VUSs) are reported in up to 4.3% of patients with PDAC and result in significant uncertainty for patients and their family members as an unknown fraction are functionally deleterious, and therefore, likely pathogenic. Functional characterization of\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    VUSs is needed to reclassify variants and inform clinical management. Twenty-nine germline\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    VUSs previously reported in patients with PDAC or in ClinVar were evaluated using a validated in vitro cell proliferation assay. Twelve of the 29\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    VUSs were functionally deleterious (11 VUSs) or potentially functionally deleterious (1 VUS) and were reclassified as likely pathogenic variants. Thus, over 40% of\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    VUSs identified in patients with PDAC are functionally deleterious and likely pathogenic. When incorporating VUSs found to be functionally deleterious, and reclassified as likely pathogenic, the prevalence of pathogenic\/likely pathogenic\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    in patients with PDAC reported in the published literature is increased to up to 4.1% of patients, depending on family history. Therefore,\n                    <jats:italic>CDKN2A<\/jats:italic>\n                    VUSs may play a significant, unappreciated role in risk of pancreatic cancer. These findings have significant implications for the counselling and care of patients and their relatives.\n                  <\/jats:p>","DOI":"10.7554\/elife.71137","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T07:15:14Z","timestamp":1641798914000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.71137","source":"Crossref","is-referenced-by-count":22,"title":["Functional CDKN2A assay identifies frequent deleterious alleles misclassified as variants of uncertain significance"],"prefix":"10.7554","volume":"11","author":[{"given":"Hirokazu","family":"Kimura","sequence":"first","affiliation":[{"name":"The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University","place":["Baltimore, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond M","family":"Paranal","sequence":"additional","affiliation":[{"name":"The Sol Goldman Pancreatic Cancer Research Center, Department of 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