{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:00:14Z","timestamp":1790758814529,"version":"4.1.0"},"reference-count":16,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Low-variant allele frequency (VAF) variants identified during germline testing may represent constitutional mosaicism or acquired somatic events restricted to hematopoietic cells. Although clonal hematopoiesis of indeterminate potential (CHIP) has emerged as an important source of interpretative pitfalls in hereditary cancer testing, its potential impact on the interpretation of CDKN1B variants has not been specifically emphasized. We aimed to determine whether low-VAF CDKN1B variants detected during routine germline testing for pituitary adenoma predisposition may represent clonal hematopoiesis rather than true constitutional alterations. We analyzed patients referred for routine genetic investigation of pituitary adenoma predisposition who has low-frequency CDKN1B variants identified in blood-derived DNA. Additional analyses were performed, including assessment of variant distribution in nonhematopoietic tissues, tumor DNA analysis, and investigation of CHIP-associated genes. Three unrelated patients carrying truncating CDKN1B variants were identified, with blood-derived VAFs ranging from 4% to 6%. Clinical presentations included 2 gonadotroph macroadenomas diagnosed later than age 70 years and 1 prolactin-secreting macroadenoma diagnosed before age 35. CDKN1B variants were absent in buccal swab DNA and from available pituitary tumor DNA. Additional pathogenic variants affecting CHIP-associated genes were identified in 2 individuals. Collectively, these findings supported a leukocyte-restricted origin of the CDKN1B variants and suggested CHIP as the most likely explanation. Low-frequency CDKN1B variants detected during blood-based germline testing should not automatically be interpreted as constitutional mosaicism or inherited endocrine tumor predisposition. Integration of tissue-specific analyses and consideration of CHIP-related findings are essential to avoid inappropriate genetic counseling, unnecessary familial investigations, and misleading surveillance recommendations.<\/jats:p>","DOI":"10.1093\/ejendo\/lvag165","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T11:47:16Z","timestamp":1787831236000},"page":"K21-K26","source":"Crossref","is-referenced-by-count":0,"title":["Low-frequency\n                    <i>CDKN1B<\/i>\n                    variants in pituitary testing: a diagnostic pitfall"],"prefix":"10.1093","volume":"195","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9835-2156","authenticated-orcid":false,"given":"Albain","family":"Chansavang","sequence":"first","affiliation":[{"name":"Institut Cochin, Inserm U1016, CNRS UMR8104, Universit\u00e9 Paris Cit\u00e9, CARPEM , Paris 75014 ,","place":["France"]},{"name":"Genetics Department, Cochin Hospital, APHP , Paris 75014 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Hematology Department, Cochin Hospital, APHP , Paris 75014 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4278-1040","authenticated-orcid":false,"given":"Emmanuelle","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Pituitary Unit, Piti\u00e9-Salp\u00eatri\u00e8re Hospital, APHP , Paris 75013 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aur\u00e9lie","family":"Toussaint","sequence":"additional","affiliation":[{"name":"Genetics Department, Cochin Hospital, APHP , Paris 75014 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alimha","family":"Godin","sequence":"additional","affiliation":[{"name":"Genetics Department, Cochin Hospital, APHP , Paris 75014 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadim","family":"Hamzaoui","sequence":"additional","affiliation":[{"name":"Institut Cochin, Inserm U1016, CNRS UMR8104, Universit\u00e9 Paris Cit\u00e9, CARPEM , Paris 75014 ,","place":["France"]},{"name":"Genetics Department, Cochin Hospital, APHP , Paris 75014 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2551-3008","authenticated-orcid":false,"given":"J\u00e9r\u00f4me","family":"Bertherat","sequence":"additional","affiliation":[{"name":"Endocrinology Department, Cochin Hospital, APHP , Paris 75014 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Kosmider","sequence":"additional","affiliation":[{"name":"Hematology Department, Cochin Hospital, APHP , Paris 75014 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Pasmant","sequence":"additional","affiliation":[{"name":"Institut Cochin, Inserm U1016, CNRS UMR8104, Universit\u00e9 Paris Cit\u00e9, CARPEM , Paris 75014 ,","place":["France"]},{"name":"Genetics Department, Institut Curie , Paris 75005 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"issue":"5","key":"2026093004241996700_lvag165-B1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1038\/nrendo.2011.40","article-title":"Pathogenesis of pituitary tumors","volume":"7","author":"Melmed","year":"2011","journal-title":"Nat Rev Endocrinol"},{"issue":"8","key":"2026093004241996700_lvag165-B2","doi-asserted-by":"publisher","first-page":"e1926","DOI":"10.1210\/clinem\/dgag195","article-title":"The germline landscape of pituitary adenomas: established and emerging predisposition genes","volume":"111","author":"Mignone","year":"2026","journal-title":"J Clin Endocrinol Metab"},{"issue":"42","key":"2026093004241996700_lvag165-B3","doi-asserted-by":"publisher","first-page":"15558","DOI":"10.1073\/pnas.0603877103","article-title":"Germ-line mutations in p27 Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans","volume":"103","author":"Pellegata","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"2026093004241996700_lvag165-B4","doi-asserted-by":"publisher","first-page":"T195","DOI":"10.1530\/ERC-17-0243","article-title":"MEN4 and CDKN1B mutations: the latest of the MEN syndromes","volume":"24","author":"Alrezk","year":"2017","journal-title":"Endocr Relat Cancer"},{"issue":"7","key":"2026093004241996700_lvag165-B5","doi-asserted-by":"publisher","first-page":"e1482","DOI":"10.1210\/clinem\/dgae055","article-title":"Beyond MEN1, when to think about MEN4? 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