{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T01:13:30Z","timestamp":1781658810611,"version":"3.54.5"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,3,25]],"date-time":"2022-03-25T00:00:00Z","timestamp":1648166400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Purpose<\/jats:title><jats:p>Contrary to BRCA pathogenic variants, recommendations for management of variants of uncertain significance (VUS) are not clear and focus more on the patient\u2019s family and personal history of cancer. Local and regional data on VUS are scarce. In this paper, we study patterns and frequency of VUS among breast cancer patients undergoing genetic testing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and Methods<\/jats:title><jats:p>Patients with breast cancer at high risk for pathogenic variants, as per the National Comprehensive Cancer Network (NCCN) guidelines, were tested at reference laboratories. Related surgical interventions were reviewed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among a group of 1,197 patients with breast cancer who underwent genetic testing and counseling, 110 (9.2%) had VUS; most (n = 79, 71.8%) were in <jats:italic>BRCA2<\/jats:italic>. Median age (range) was 39 (25\u201366) years with 65 (59.1%) patients who were 40 years or younger at diagnosis. Among 103 patients with non-metastatic disease, 48 (46.6%) had breast-conserving surgery (BCS) while only 5 (4.9%) had bilateral mastectomies; all were due to bilateral disease and not prophylactic. VUS diagnosis was known prior to initial surgery in 34 (33.0%) patients; 11 (32.4%) of them had BCS only. Over the study period, only one VUS variant was upgraded to \u201clikely positive.\u201d The recent introduction of multiple-gene panel testing had resulted in a surge in VUS rate (22.2%) in genes other than <jats:italic>BRCA1<\/jats:italic> or <jats:italic>BRCA2<\/jats:italic>, like <jats:italic>PALB2, CHEK2<\/jats:italic>, and <jats:italic>ATM.<\/jats:italic><\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Rates of VUS are relatively high and increasing, mostly in non-<jats:italic>BRCA1<\/jats:italic> or <jats:italic>BRCA2<\/jats:italic>, and this had no impact on the therapeutic or prophylactic surgical decisions. Adherence to guidelines is extremely important to avoid unnecessary procedures.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2022.673094","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T12:15:46Z","timestamp":1648556146000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Rates of Variants of Uncertain Significance Among Patients With Breast Cancer Undergoing Genetic Testing: Regional Perspectives"],"prefix":"10.3389","volume":"12","author":[{"given":"Hikmat","family":"Abdel-Razeq","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faris","family":"Tamimi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama","family":"Abujamous","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashid","family":"Abdel-Razeq","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Abunasser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Edaily","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hazem","family":"Abdulelah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razan Abu","family":"Khashabeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayan","family":"Bater","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,3,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1200\/JGO.19.00279","article-title":"Breast Cancer Care in Jordan","volume":"6","author":"Abdel-Razeq","year":"2020","journal-title":"JCO Global Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer Statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"Cancer J Clin"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.0424","article-title":"Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer","volume":"3","author":"Couch","year":"2017","journal-title":"JAMA Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4137\/BCBCR.S18715","article-title":"Hereditary Breast Cancer: Clinical, Pathological and Molecular Characteristics","volume":"8","author":"Larsen","year":"2014","journal-title":"Breast Cancer: Basic Clin Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/378789a0","article-title":"Identification of the Breast Cancer Susceptibility Gene BRCA2","volume":"378","author":"Wooster","year":"1995","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1126\/science.7545954","article-title":"A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1","volume":"266","author":"Miki","year":"1994","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.65.0747","article-title":"Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer","volume":"34","author":"Tung","year":"2016","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.09.1066","article-title":"Meta-Analysis of BRCA1 and BRCA2 Penetrance","volume":"25","author":"Chen","year":"2007","journal-title":"J Clin Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djt095","article-title":"Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE. 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