{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T22:40:10Z","timestamp":1792017610995,"version":"4.4.0"},"reference-count":22,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Pathogenic variants in the mismatch repair genes are associated with an elevated lifetime risk of colorectal cancer (CRC). We previously identified two variants of uncertain significance (VUS) in the <jats:italic>MLH1<\/jats:italic> gene, c.696_698del, p.(Cys233del) and c.1919C &gt; G, p.(Pro640Arg), in Danish families with numerous occurrences of CRC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To reclassify the variants we collected clinical data, initiated tumor and co\u2010segregation analysis, and performed RNA splicing analysis, subcellular localization, and protein stability studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The functional analysis revealed that the c.696_698del, p.(Cys233del) variant had an effect at the RNA level, on subcellular localization, and on protein stability, while the c.1919C &gt; G, p.(Pro640Arg) variant showed decreased expression in localization studies and decreased protein stability. These results suggest both variants disrupt DNA mismatch repair.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>By applying all collected data and functional results we propose to reclassify the c.696_698del, p.(Cys233del) and the c.1919C &gt; G, p.(Pro640Arg) variants as likely pathogenic (class 4) using MMR gene\u2010specific ACMG\/AMP guidelines. Consequently, the two <jats:italic>MLH1<\/jats:italic> variants can now be used for risk assessment of variant carriers, while family members without the variants can be excluded from intensified cancer surveillance and follow population recommendations.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.70026","type":"journal-article","created":{"date-parts":[[2024,11,16]],"date-time":"2024-11-16T04:23:56Z","timestamp":1731731036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Reclassification of Two <i>MLH1<\/i> Variants of Uncertain Significance Utilizing Clinical and Functional Data"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7719-4673","authenticated-orcid":false,"given":"Jane H\u00fcbertz","family":"Frederiksen","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulf","family":"Birkedal","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5522-4335","authenticated-orcid":false,"given":"Sarah","family":"Bachmann","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth Victoria","family":"Eliesen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene Juel","family":"Rasmussen","sequence":"additional","affiliation":[{"name":"Center for Healthy Aging, Department of Cellular and Molecular Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katja Venborg","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Hospital Littlebelt University of Southern Denmark  Vejle Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lana","family":"Al\u2010Zehhawi","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Zealand University Hospital Region Zealand  Roskilde Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne E.","family":"Boonen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lotte","family":"Krogh","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Odense University Hospital  Odense Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"R\u00f8nlund","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Hospital Littlebelt University of Southern Denmark  Vejle Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2395-8281","authenticated-orcid":false,"given":"Lise","family":"Graversen","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Aarhus University Hospital  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannie","family":"Assenholt","sequence":"additional","affiliation":[{"name":"MOMA  Aarhus Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjeld","family":"Schmiegelow","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Adolescent Medicine Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Wadt","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne\u2010Marie","family":"Gerdes","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Rigshospitalet Copenhagen University Hospital  Copenhagen Denmark"},{"name":"Department of Clinical Medicine University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas v. 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