{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:14:07Z","timestamp":1792019647914,"version":"4.4.0"},"reference-count":27,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec007\">\n<jats:title>Introduction<\/jats:title>\n<jats:p>Laboratories will occasionally reclassify a VUS to pathogenic (P) or likely pathogenic (LP), making it clinically actionable. Here, we aim to characterize the frequency of this reclassification in genes tested routinely during preconception counseling in order to help guide reproductive decision making.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec008\">\n<jats:title>Design<\/jats:title>\n<jats:p>Utilizing the American College of Medical Genetics (ACMG) 113-gene pre-conception panel, we conducted data analysis from ClinVar Miner (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinvarminer.genetics.utah.edu\/\" xlink:type=\"simple\">https:\/\/clinvarminer.genetics.utah.edu\/<\/jats:ext-link>). The numbers of VUS\u2019s reported for each gene were recorded over a 3-year period (2019, 2021, &amp; 2022). In addition, data on the number of VUS\u2019s <jats:italic>in conflict<\/jats:italic> (VUS\/P and VUS\/LP) were recorded. The 10 genes with the most VUS\u2019s and the genes with the most frequent reporting discordance were compared over the 3 years,<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec009\">\n<jats:title>Results<\/jats:title>\n<jats:p>There was a 103% increase in the number of VUS\u2019s reported (2019: 13,278, 2021: 22,434, 2022: 26,965) and a 235% increase in the number of VUS\u2019s in conflict (2019:387, 2021: 946, 2022:1297). The overall percent conflict increased significantly (2019: 2.9% vs. 2022: 4.8%). Nine genes among the top 10 with the most frequent VUS\u2019s remained the same over the 3-year period, while five out of the ten most frequent genes with VUS\u2019s in conflict remained the same.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec010\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>The rate of conflicting reporting of a VUS has increased in 3 years and is currently at 4.8%. A potential upgrade of a VUS to pathogenic or likely pathogenic may turn the variant \u201cactionable,\u201d justifying testing embryos for the variant through PGT-M.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0308771","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T17:47:48Z","timestamp":1748368068000},"page":"e0308771","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["The impact of VUS reclassification on reproductive decision making"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7516-9810","authenticated-orcid":true,"given":"Alexandra","family":"Peyser","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenan","family":"Onel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avner","family":"Hershlag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"issue":"5","key":"pone.0308771.ref001","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":"S Richards","year":"2015","journal-title":"Genet Med"},{"issue":"1","key":"pone.0308771.ref002","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/jgc4.1482","article-title":"Offering preimplantation genetic testing for monogenic disorders (PGT-M) for conditions with reduced penetrance or variants of uncertain significance: Ethical insight from U.S. laboratory genetic counselors","volume":"31","author":"A Porto","year":"2022","journal-title":"J Genet Couns"},{"issue":"10","key":"pone.0308771.ref003","doi-asserted-by":"crossref","DOI":"10.1001\/jamanetworkopen.2023.39571","article-title":"Rates and classification of variants of uncertain significance in hereditary disease genetic testing","volume":"6","author":"E Chen","year":"2023","journal-title":"JAMA Netw Open"},{"issue":"5","key":"pone.0308771.ref004","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1016\/j.ajhg.2016.09.015","article-title":"Reassessment of genomic sequence variation to harmonize interpretation for personalized medicine","volume":"99","author":"KB Garber","year":"2016","journal-title":"Am J Hum Genet"},{"issue":"10","key":"pone.0308771.ref005","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1038\/s41436-021-01203-z","article-title":"Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG)","volume":"23","author":"AR Gregg","year":"2021","journal-title":"Genet Med"},{"issue":"2","key":"pone.0308771.ref006","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1080\/13669877.2016.1215344","article-title":"Mapping uncertainty in genomics","volume":"21","author":"HC Howard","year":"2017","journal-title":"J Risk Res"},{"issue":"8","key":"pone.0308771.ref007","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1038\/gim.2016.212","article-title":"A taxonomy of medical uncertainties in clinical genome sequencing","volume":"19","author":"PKJ Han","year":"2017","journal-title":"Genet Med"},{"issue":"11","key":"pone.0308771.ref008","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1016\/j.hrthm.2015.07.002","article-title":"Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain\/unknown significance issue","volume":"12","author":"MJ Ackerman","year":"2015","journal-title":"Heart Rhythm"},{"issue":"11","key":"pone.0308771.ref009","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/gim.2013.133","article-title":"Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium","volume":"15","author":"JS Berg","year":"2013","journal-title":"Genet Med"},{"issue":"10","key":"pone.0308771.ref010","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1001\/jama.2014.1717","article-title":"Clinical interpretation and implications of whole-genome sequencing","volume":"311","author":"FE Dewey","year":"2014","journal-title":"JAMA"},{"issue":"6","key":"pone.0308771.ref011","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.fertnstert.2018.04.003","article-title":"Use of preimplantation genetic testing for monogenic defects (PGT-M) for adult-onset conditions: an Ethics Committee opinion","volume":"109","author":"Ethics Committee of the American Society for Reproductive Medicine. Electronic address: ASRM@asrm.org, Ethics Committee of the American Society for Reproductive Medicine","year":"2018","journal-title":"Fertil Steril"},{"issue":"4","key":"pone.0308771.ref012","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1097\/AOG.0000000000004062","article-title":"Obstetric and perinatal outcomes in pregnancies conceived after preimplantation genetic testing for monogenetic diseases","volume":"136","author":"B Feldman","year":"2020","journal-title":"Obstet Gynecol"},{"key":"pone.0308771.ref013","article-title":"Indications and management of preimplantation genetic testing for monogenic conditions: a committee opinion","year":"2023","journal-title":"Fertil Steril"},{"issue":"3","key":"pone.0308771.ref014","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1007\/s10815-020-02055-3","article-title":"Preimplantation genetic testing (PGT) for copy number variants of uncertain significance (CNV- VUS) in the genomic era: to do or not to do?","volume":"38","author":"K Rotshenker-Olshinka","year":"2021","journal-title":"J Assist Reprod Genet"},{"issue":"6","key":"pone.0308771.ref015","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1111\/aogs.13813","article-title":"\u201cIt\u2019s probably nothing, but\u2026\u201d Couples\u2019 experiences of pregnancy following an uncertain prenatal genetic result","volume":"99","author":"S Lou","year":"2020","journal-title":"Acta Obstet Gynecol Scand"},{"issue":"9","key":"pone.0308771.ref016","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1111\/bioe.12932","article-title":"To offer or request? Disclosing variants of uncertain significance in prenatal testing","volume":"35","author":"G Watts","year":"2021","journal-title":"Bioethics"},{"issue":"12","key":"pone.0308771.ref017","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/gim.2014.48","article-title":"Comparison of risk management strategies between women testing positive for a BRCA variant of unknown significance and women with known BRCA deleterious mutations.","volume":"16","author":"C Garcia","year":"2014","journal-title":"Genet Med"},{"issue":"1","key":"pone.0308771.ref018","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s10689-018-0086-2","article-title":"Physician interpretation of variants of uncertain significance","volume":"18","author":"SK Macklin","year":"2019","journal-title":"Fam Cancer"},{"issue":"2","key":"pone.0308771.ref019","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1007\/s12687-019-00434-7","article-title":"Patients\u2019 views on variants of uncertain significance across indications","volume":"11","author":"K Clift","year":"2020","journal-title":"J Community Genet"},{"issue":"1","key":"pone.0308771.ref020","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s13073-019-0688-9","article-title":"Is \u201clikely pathogenic\u201d really 90% likely? Reclassification data in ClinVar","volume":"11","author":"SM Harrison","year":"2019","journal-title":"Genome Med"},{"issue":"1","key":"pone.0308771.ref021","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13045-020-01010-0","article-title":"Prevalence and reclassification of BRCA1 and BRCA2 variants in a large, unselected Chinese Han breast cancer cohort","volume":"14","author":"Y Liu","year":"2021","journal-title":"J Hematol Oncol"},{"issue":"5","key":"pone.0308771.ref022","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1038\/s41436-019-0740-6","article-title":"Systematic misclassification of missense variants in BRCA1 and BRCA2 \u201ccoldspots\u201d","volume":"22","author":"JN Dines","year":"2020","journal-title":"Genet Med"},{"issue":"7","key":"pone.0308771.ref023","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1634\/theoncologist.2016-0431","article-title":"Clinical variant classification: a comparison of public databases and a commercial testing laboratory","volume":"22","author":"W Gradishar","year":"2017","journal-title":"Oncologist"},{"issue":"3","key":"pone.0308771.ref024","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/gim.2017.212","article-title":"Clinically impactful differences in variant interpretation between clinicians and testing laboratories: a single-center experience","volume":"20","author":"A Bland","year":"2018","journal-title":"Genet Med"},{"issue":"1","key":"pone.0308771.ref025","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.xfre.2022.12.005","article-title":"A case series of adrenoleukodystrophy in children conceived through in vitro fertilization with an egg donor","volume":"4","author":"C Chang","year":"2023","journal-title":"F&S Reports"},{"issue":"1","key":"pone.0308771.ref026","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1186\/s12967-024-05508-w","article-title":"Accuracy of renovo predictions on variants reclassified over time","volume":"22","author":"E Bonetti","year":"2024","journal-title":"J Transl Med"},{"issue":"10","key":"pone.0308771.ref027","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1038\/gim.2017.60","article-title":"Sources of discordance among germ-line variant classifications in ClinVar","volume":"19","author":"S Yang","year":"2017","journal-title":"Genet Med"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0308771","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T17:47:54Z","timestamp":1748368074000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0308771"}},"subtitle":[],"editor":[{"given":"Nejat","family":"Mahdieh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":27,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0308771","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,27]]}}}