{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T04:55:05Z","timestamp":1792644905853,"version":"4.5.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T00:00:00Z","timestamp":1720569600000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,8,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite recent efforts to issue clinical guidelines outlining strategies to define the pathogenicity of genomic variants, there is currently no standardized framework for which to make these assertions. This review does not present a step-by-step methodology, but rather takes a holistic approach to discuss many aspects which should be taken into consideration when determining variant pathogenicity. Categorization should be curated to reflect relevant findings within the scope of the specific medical context. Functional characterization should evaluate all available information, including results from literature reviews, different classes of genomic data repositories, and applicable computational predictive algorithms. This article further proposes a multidimensional view to infer pathogenic status from many genomic measurements across multiple axes. Notably, tumor suppressors and oncogenes exhibit fundamentally different biology which helps refine the importance of effects on splicing, mutation interactions, copy number thresholds, rearrangement annotations, germline status, and genome-wide signatures. Understanding these relevant datapoints with thoughtful perspective could aid in the reclassification of variants of unknown significance (VUS), which are ambiguously understood and currently have uncertain clinical implications. Ongoing assessments of VUS examining these relevant biological axes could lead to more accurate classification of variant pathogenicity interpretation in diagnostic oncology.<\/jats:p>","DOI":"10.1093\/oncolo\/oyae149","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T12:28:49Z","timestamp":1717072129000},"page":"658-666","source":"Crossref","is-referenced-by-count":17,"title":["Understanding variants of unknown significance and classification of genomic alterations"],"prefix":"10.1093","volume":"29","author":[{"given":"Dean C","family":"Pavlick","sequence":"first","affiliation":[{"name":"Department of Computational Discovery, Foundation Medicine, Inc. , Boston, MA , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett M","family":"Frampton","sequence":"additional","affiliation":[{"name":"Department of Computational Discovery, Foundation Medicine, Inc. , Boston, MA , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey R","family":"Ross","sequence":"additional","affiliation":[{"name":"Department of Pathology, Foundation Medicine, Inc. , Boston, MA , United States , and"},{"name":"Departments of Pathology, Medicine (Oncology), and Urology, Upstate Medical University , Syracuse, NY , United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,9]]},"reference":[{"key":"2024080521155364600_CIT0001","doi-asserted-by":"crossref","DOI":"10.1093\/oncolo\/oyae135","article-title":"Variants of uncertain significance (VUS) in precision oncology: nuance or nuisance?","author":"Mellgard","year":"2024","journal-title":"Oncologist."},{"issue":"5","key":"2024080521155364600_CIT0002","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"issue":"9","key":"2024080521155364600_CIT0003","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1016\/j.gim.2022.05.002","article-title":"Reclassification of clinically-detected sequence variants: Framework for genetic clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group UK)","volume":"24","author":"Loong","year":"2022","journal-title":"Genet Med"},{"issue":"1","key":"2024080521155364600_CIT0004","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jmoldx.2016.10.002","article-title":"Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists","volume":"19","author":"Li","year":"2017","journal-title":"J Mol Diagn"},{"issue":"5","key":"2024080521155364600_CIT0005","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.gim.2022.01.001","article-title":"Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC)","volume":"24","author":"Horak","year":"2022","journal-title":"Genet Med"},{"issue":"7809","key":"2024080521155364600_CIT0006","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"issue":"7571","key":"2024080521155364600_CIT0007","first-page":"68","article-title":"The 1000 Genomes Project Consortium. 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