{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T17:52:04Z","timestamp":1784742724515,"version":"3.55.0"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T00:00:00Z","timestamp":1674086400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Sigrid Jus\u00e9lius foundation"},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["307808"],"award-info":[{"award-number":["307808"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Cancer Foundation of Finland sr"},{"name":"University of Oulu including Oulu University Hospital"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Familial Cancer"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>CHEK2<\/jats:italic> is a well-established breast cancer susceptibility gene. The most frequent pathogenic <jats:italic>CHEK2<\/jats:italic> variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is <jats:italic>CHEK2<\/jats:italic> c.1312 G\u2009&gt;\u2009T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of <jats:italic>CHEK2<\/jats:italic> p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen <jats:italic>CHEK2<\/jats:italic> p.(Asp438Tyr) carriers were identified (14\/2284, 0.6%, P\u2009=\u20090.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2\/281, 0.7%, P\u2009=\u20091.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12\/2003, 0.6%, P\u2009=\u20090.66). This frequency did not differ from the frequency in the general population (10\/1299, 0.8%). No <jats:italic>CHEK2<\/jats:italic> p.(Asp438Tyr) homozygotes were identified. Our results indicate that <jats:italic>CHEK2<\/jats:italic> p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the <jats:italic>CHEK2<\/jats:italic> p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer.<\/jats:p>","DOI":"10.1007\/s10689-023-00327-2","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T01:41:20Z","timestamp":1674092480000},"page":"291-294","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition"],"prefix":"10.1007","volume":"22","author":[{"given":"Timo A.","family":"Kumpula","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Koivuluoma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Soikkonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Vorimo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka","family":"Moilanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Winqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuomo","family":"Mantere","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Outi","family":"Kuismin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katri","family":"Pylk\u00e4s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,1,19]]},"reference":[{"key":"327_CR1","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1016\/j.dnarep.2004.03.033","volume":"3","author":"J Ahn","year":"2004","unstructured":"Ahn J, Urist M, Prives C (2004) The Chk2 protein kinase. DNA Repair (Amst) 3:1039\u20131047","journal-title":"DNA Repair (Amst)"},{"key":"327_CR2","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1038\/35103059","volume":"2","author":"J Bartek","year":"2001","unstructured":"Bartek J, Falck J, Lukas J (2001) Chk2 kinase - A busy messenger. Nat Rev Mol Cell Biol 2:877\u2013886. https:\/\/doi.org\/10.1038\/35103059","journal-title":"Nat Rev Mol Cell Biol"},{"key":"327_CR3","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/ng879","volume":"31","author":"H Meijers-Heijboer","year":"2002","unstructured":"Meijers-Heijboer H, van den Ouweland A, Klijn J et al (2002) Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations: the CHEK2-breast cancer consortium. Nat Genet 31:55\u201359. https:\/\/doi.org\/10.1038\/ng879","journal-title":"Nat Genet"},{"key":"327_CR4","doi-asserted-by":"publisher","unstructured":"Vahteristo P, Bartkova J, Eerola H et al (2002) A CHEK2 genetic variant contributing. to a Substantial Fraction of Familial Breast Cancer. Am J Hum Genet 71:432-438. https:\/\/doi.org\/10.1086\/341943","DOI":"10.1086\/341943"},{"key":"327_CR5","doi-asserted-by":"publisher","unstructured":"le Calvez-Kelm F, Lesueur F, Damiola F et al (2011) Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res 13. https:\/\/doi.org\/10.1186\/bcr2810","DOI":"10.1186\/bcr2810"},{"key":"327_CR6","doi-asserted-by":"publisher","first-page":"2661","DOI":"10.1002\/ijc.23026","volume":"121","author":"DW Bell","year":"2007","unstructured":"Bell DW, Kim SH, Godwin AK et al (2007) Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts. Int J Cancer 121:2661\u20132667. https:\/\/doi.org\/10.1002\/ijc.23026","journal-title":"Int J Cancer"},{"key":"327_CR7","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1002\/humu.23728","volume":"40","author":"A Delimitsou","year":"2019","unstructured":"Delimitsou A, Fostira F, Kalfakakou D et al (2019) Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat 40:631\u2013648. https:\/\/doi.org\/10.1002\/humu.23728","journal-title":"Hum Mutat"},{"key":"327_CR8","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1002\/ijc.32385","volume":"145","author":"P Kleiblova","year":"2019","unstructured":"Kleiblova P, Stolarova L, Krizova K et al (2019) Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer 145:1782\u20131797. https:\/\/doi.org\/10.1002\/ijc.32385","journal-title":"Int J Cancer"},{"key":"327_CR9","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G et al (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581:434\u2013443. https:\/\/doi.org\/10.1038\/s41586-020-2308-7","journal-title":"Nature"},{"key":"327_CR10","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1086\/301880","volume":"62","author":"P Huusko","year":"1998","unstructured":"Huusko P, P\u00e4\u00e4kk\u00f6nen K, Launonen V et al (1998) Evidence of founder mutations in finnish BRCA1 and BRCA2 families. Am J Hum Genet 62:1544\u20131548","journal-title":"Am J Hum Genet"},{"key":"327_CR11","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1038\/nature05609","volume":"446","author":"H Erkko","year":"2007","unstructured":"Erkko H, Xia B, Nikkil\u00e4 J et al (2007) A recurrent mutation in PALB2 in finnish cancer families. Nature 446:316\u2013319. https:\/\/doi.org\/10.1038\/nature05609","journal-title":"Nature"},{"key":"327_CR12","doi-asserted-by":"publisher","unstructured":"Mantere T, Winqvist R, Kauppila S et al (2016) Targeted next-generation sequencing identifies a recurrent mutation in MCPH1 associating with Hereditary breast Cancer susceptibility. PLoS Genet 12. https:\/\/doi.org\/10.1371\/journal.pgen.1005816","DOI":"10.1371\/journal.pgen.1005816"},{"key":"327_CR13","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s10549-010-1050-5","volume":"123","author":"J Brunet","year":"2010","unstructured":"Brunet J (2010) Hereditary breast cancer and genetic counseling in young women. Breast Cancer Res Treat 123:7\u20139. https:\/\/doi.org\/10.1007\/s10549-010-1050-5","journal-title":"Breast Cancer Res Treat"},{"key":"327_CR14","doi-asserted-by":"publisher","unstructured":"Koivuluoma S, Tervasm\u00e4ki A, Kauppila S et al (2021) Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer. Eur J Cancer 143. https:\/\/doi.org\/10.1016\/j.ejca.2020.10.033","DOI":"10.1016\/j.ejca.2020.10.033"},{"key":"327_CR15","doi-asserted-by":"publisher","unstructured":"Dorling L, Carvalho S, Allen J et al (2022) Breast cancer risks associated with missense variants in breast cancer susceptibility genes. Genome Med 14. https:\/\/doi.org\/10.1186\/s13073-022-01052-8","DOI":"10.1186\/s13073-022-01052-8"},{"key":"327_CR16","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1158\/0008-5472.CAN-21-1845","volume":"82","author":"RACM Boonen","year":"2022","unstructured":"Boonen RACM, Wiegant WW, Celosse N et al (2022) Functional analysis identifies damaging CHEK2 missense Variants Associated with increased Cancer risk. Cancer Res 82:615\u2013631. https:\/\/doi.org\/10.1158\/0008-5472.CAN-21-1845","journal-title":"Cancer Res"}],"container-title":["Familial Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-023-00327-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10689-023-00327-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10689-023-00327-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,16]],"date-time":"2023-06-16T04:26:07Z","timestamp":1686889567000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10689-023-00327-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,19]]},"references-count":16,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["327"],"URL":"https:\/\/doi.org\/10.1007\/s10689-023-00327-2","relation":{},"ISSN":["1389-9600","1573-7292"],"issn-type":[{"value":"1389-9600","type":"print"},{"value":"1573-7292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,19]]},"assertion":[{"value":"22 November 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 January 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 January 2023","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 authors declare that there is no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}