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Pathogenic missense and truncating\n                    <jats:italic>TINF2<\/jats:italic>\n                    mutations are causative for dyskeratosis congenita (DC), a rare, dominantly inherited bone marrow failure syndrome characterized by mucocutaneous abnormalities and cancer predisposition. Recent reports indicate that specific\n                    <jats:italic>TINF2<\/jats:italic>\n                    truncating mutations act as high penetrance cancer predisposition alleles outside DC context, including breast cancer in their tumor spectrum. Here, we have evaluated the role of germline mutations in\n                    <jats:italic>TINF2<\/jats:italic>\n                    and other shelterin genes in inherited breast cancer susceptibility using exome sequencing data from 98 Northern Finnish breast cancer cases with indication of inherited disease predisposition as a discovery cohort. A single protein truncating variant,\n                    <jats:italic>TINF2<\/jats:italic>\n                    p.Tyr312Ter, was identified in one of the cases (1\/98), and four more carriers were observed in the subsequently genotyped unselected breast cancer cohort (4\/1904). None of the carriers were reported to have DC.\n                    <jats:italic>TINF2<\/jats:italic>\n                    p.Tyr312Ter resulted in stable short form of mRNA transcript, and normal telomere length has been indicated by a recent report. Although recurrent in cases (total of 5\/2095),\n                    <jats:italic>TINF2<\/jats:italic>\n                    p.Tyr312Ter is also present in Finnish population controls (8\/12,517), and the observed 4-fold higher frequency in cases falls at most into the range of moderate breast cancer risk alleles (OR 3.74, 95% CI 1.22\u201311.45, p\u2009=\u20090.029). Current results indicate that not all\n                    <jats:italic>TINF2<\/jats:italic>\n                    truncating variants are high cancer risk alleles and add further evidence that different\n                    <jats:italic>TINF2<\/jats:italic>\n                    mutations can have very diverse effects on the disease phenotype.\n                  <\/jats:p>","DOI":"10.1007\/s10689-022-00295-z","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T23:31:52Z","timestamp":1653003112000},"page":"13-17","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Truncating TINF2 p.Tyr312Ter variant and inherited breast cancer susceptibility"],"prefix":"10.1007","volume":"22","author":[{"given":"Susanna","family":"Koivuluoma","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Vorimo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiina M.","family":"Mattila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Tervasm\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Kumpula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Kuismin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Winqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"Moilanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomo","family":"Mantere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2449-0521","authenticated-orcid":false,"given":"Katri","family":"Pylk\u00e4s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,5,20]]},"reference":[{"key":"295_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-232","author":"H Xin","year":"2008","unstructured":"Xin H, Liu D, Songyang Z (2008) The telosome\/shelterin complex and its functions. Genome Biol. https:\/\/doi.org\/10.1186\/gb-2008-9-9-232","journal-title":"Genome Biol"},{"key":"295_CR2","doi-asserted-by":"publisher","unstructured":"de Lange T (2018) Shelterin-Mediated Telomere Protection. https:\/\/doi.org\/10.1146\/annurev-genet-032918","DOI":"10.1146\/annurev-genet-032918"},{"issue":"9","key":"295_CR3","doi-asserted-by":"publisher","first-page":"3594","DOI":"10.1182\/blood-2008-05-153445","volume":"112","author":"AJ Walne","year":"2008","unstructured":"Walne AJ, Vulliamy T, Beswick R, Kirwan M, Dokal I (2008) TINF2 mutations result in very short telomeres: Analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood 112(9):3594\u20133600. https:\/\/doi.org\/10.1182\/blood-2008-05-153445","journal-title":"Blood"},{"issue":"5","key":"295_CR4","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1111\/j.1399-0004.2011.01658.x","volume":"81","author":"GS Sasa","year":"2012","unstructured":"Sasa GS, Ribes-Zamora A, Nelson ND, Bertuch AA (2012) Three novel truncating TINF2 mutations causing severe dyskeratosis congenita in early childhood. Clin Genet 81(5):470\u2013478. https:\/\/doi.org\/10.1111\/j.1399-0004.2011.01658.x","journal-title":"Clin Genet"},{"key":"295_CR5","doi-asserted-by":"publisher","unstructured":"Savage SA, Alter BP (2009, April) Dyskeratosis Congenita. 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Thyroid 30(2):204\u2013213. https:\/\/doi.org\/10.1089\/thy.2019.0156","journal-title":"Thyroid"},{"key":"295_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.7554\/ELIFE.61235","volume":"9","author":"I Schmutz","year":"2020","unstructured":"Schmutz I, Mensenkamp AR, Takai KK, Haadsma M, Spruijt L, de Voer RM, de Lange T (2020) Tinf2 is a haploinsufficient tumor suppressor that limits telomere length. eLife 9:1\u201320. https:\/\/doi.org\/10.7554\/ELIFE.61235","journal-title":"eLife"},{"key":"295_CR8","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.ejca.2020.10.033","volume":"143","author":"S Koivuluoma","year":"2021","unstructured":"Koivuluoma S, Tervasm\u00e4ki A, Kauppila S, Winqvist R, Kumpula T, Kuismin O, Pylk\u00e4s K (2021) Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer. Eur J Cancer 143:46\u201351. https:\/\/doi.org\/10.1016\/j.ejca.2020.10.033","journal-title":"Eur J Cancer"},{"issue":"6","key":"295_CR9","doi-asserted-by":"publisher","first-page":"931","DOI":"10.4161\/cc.8.6.7941","volume":"8","author":"PG Kaminker","year":"2009","unstructured":"Kaminker PG, Kim SH, Desprez PY, Campisi J (2009) A novel form of the telomere-associated protein TIN2 localizes to the nuclear matrix. Cell Cycle 8(6):931\u2013939. https:\/\/doi.org\/10.4161\/cc.8.6.7941","journal-title":"Cell Cycle"},{"key":"295_CR10","doi-asserted-by":"publisher","unstructured":"Hollestelle A, Wasielewski M, Martens JWM, Schutte M (2010, June) Discovering moderate-risk breast cancer susceptibility genes. 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Lippincott Williams and Wilkins. https:\/\/doi.org\/10.1212\/NXG.0000000000000532","DOI":"10.1212\/NXG.0000000000000532"}],"container-title":["Familial Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-022-00295-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10689-022-00295-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-022-00295-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T10:46:13Z","timestamp":1673606773000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10689-022-00295-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,20]]},"references-count":11,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2023,1]]}},"alternative-id":["295"],"URL":"https:\/\/doi.org\/10.1007\/s10689-022-00295-z","relation":{},"ISSN":["1389-9600","1573-7292"],"issn-type":[{"value":"1389-9600","type":"print"},{"value":"1573-7292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,20]]},"assertion":[{"value":"9 February 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2022","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 May 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study included informed consent from all participating individuals, and it was approved by the Ethical Board of the North Ostrobothnia Health Care District (100\/2016).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"The authors declare that there is no conflict of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}