{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:19:18Z","timestamp":1787066358408,"version":"build-2736575974"},"reference-count":27,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T00:00:00Z","timestamp":1710288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>POT1 (Protection of Telomeres 1) is a key component of the six-membered shelterin complex that plays a critical role in telomere protection and length regulation. Germline variants in the POT1 gene have been implicated in predisposition to cancer, primarily to melanoma and chronic lymphocytic leukemia (CLL). We report the identification of POT1 p.(I78T), previously ranked with conflicting interpretations of pathogenicity, as a founder pathogenic variant among Ashkenazi Jews (AJs) and describe its unique clinical landscape. A directed database search was conducted for individuals referred for genetic counselling from 2018 to 2023. Demographic, clinical, genetic, and pathological data were collected and analyzed. Eleven carriers, 25 to 67 years old, from ten apparently unrelated families were identified. Carriers had a total of 30 primary malignancies (range 1\u20136); nine carriers (82%) had recurrent melanoma between the ages of 25 and 63 years, three carriers (27%) had desmoid tumors, three (27%) had papillary thyroid cancer (PTC), and five women (63% of female carriers) had breast cancer between the ages of 44 and 67 years. Additional tumors included CLL; sarcomas; endocrine tumors; prostate, urinary, and colorectal cancers; and colonic polyps. A review of a local exome database yielded an allelic frequency of the variant of 0.06% among all ethnicities and of 0.25% in AJs. A shared haplotype was found in all carriers tested. POT1 p.(I78T) is a founder disease-causing variant associated with early-onset melanoma and additional various solid malignancies with a high tumor burden. We advocate testing for this variant in high-risk patients of AJ descent. The inclusion of POT1 in germline panels for various types of cancer is warranted.<\/jats:p>","DOI":"10.3390\/genes15030355","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T13:23:11Z","timestamp":1710336191000},"page":"355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies"],"prefix":"10.3390","volume":"15","author":[{"given":"Aasem","family":"Abu Shtaya","sequence":"first","affiliation":[{"name":"Recanati Genetics Institute, Rabin Medical Center\u2014Beilinson Hospital, Petach Tikva 4941492, Israel"},{"name":"Unit of Gastroenterology, Lady Davis Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inbal","family":"Kedar","sequence":"additional","affiliation":[{"name":"Recanati Genetics Institute, Rabin Medical 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Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirley","family":"Polager-Modan","sequence":"additional","affiliation":[{"name":"Genetics Institute, Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nitzan","family":"Keidar","sequence":"additional","affiliation":[{"name":"Pediatric Genetic Unit, Schneider Children\u2019s Medical Center of Israel, Petch Tikva 4920235, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gili","family":"Reznick Levi","sequence":"additional","affiliation":[{"name":"Genetics Institute, Rambam Health Care Campus, Haifa 3525408, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zohar","family":"Levi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Division of Gastroenterology, Rabin Medical Center\u2014Beilinson Hospital, Petach Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamar","family":"Yablonski-Peretz","sequence":"additional","affiliation":[{"name":"Oncology Institute, Hadassah Medical Center, Jerusalem 9112001, Israel"},{"name":"Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9190500, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad","family":"Mahamid","sequence":"additional","affiliation":[{"name":"Department of Surgery B, Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ori","family":"Segol","sequence":"additional","affiliation":[{"name":"Unit of Gastroenterology, Lady Davis Carmel Medical Center, Haifa 3436212, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reut","family":"Matar","sequence":"additional","affiliation":[{"name":"Recanati Genetics Institute, Rabin Medical Center\u2014Beilinson Hospital, Petach Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifat","family":"Bareli","sequence":"additional","affiliation":[{"name":"Recanati Genetics Institute, Rabin Medical Center\u2014Beilinson Hospital, Petach Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noy","family":"Azoulay","sequence":"additional","affiliation":[{"name":"Recanati Genetics Institute, Rabin Medical Center\u2014Beilinson Hospital, Petach Tikva 4941492, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9855-9472","authenticated-orcid":false,"given":"Yael","family":"Goldberg","sequence":"additional","affiliation":[{"name":"Recanati Genetics Institute, Rabin Medical Center\u2014Beilinson Hospital, Petach Tikva 4941492, Israel"},{"name":"Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.yexcr.2012.09.005","article-title":"Telomeres-Structure, Function, and Regulation","volume":"319","author":"Lu","year":"2013","journal-title":"Exp. 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