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Genetic testing identified two new\n                    <jats:italic>MLH1<\/jats:italic>\n                    c.-42\u00a0C\u2009&gt;\u2009T index cases from Australia and the USA. Clinicopathologic and molecular characterisation of tumour and non-neoplastic tissues was performed to investigate the potential mechanism of pathogenesis of this variant. The male Australian proband developed MLH1-deficient,\n                    <jats:italic>BRAF<\/jats:italic>\n                    p.V600 wildtype, CIMP-negative colon cancer at 61 years.\n                    <jats:italic>MLH1<\/jats:italic>\n                    monoallelic methylation and a somatic pathogenic mutation,\n                    <jats:italic>MLH1<\/jats:italic>\n                    c.1122_1126dup p.Asp376Valfs*27, were identified in his tumour. Droplet digital PCR (ddPCR) detected mosaic\n                    <jats:italic>MLH1<\/jats:italic>\n                    methylation in normal colonic mucosa adjacent to the cancer (3.7%) with lower levels in blood (0.07%) and saliva (0.09%). The USA proband developed MLH1-deficient endometrial cancer at 38 years with\n                    <jats:italic>MLH1<\/jats:italic>\n                    monoallelic methylation and loss-of-heterozygosity of the wildtype c.-42\u00a0C allele. No evidence of\n                    <jats:italic>MLH1<\/jats:italic>\n                    methylation was found by ddPCR in normal tissues.\n                    <jats:italic>MLH1<\/jats:italic>\n                    c.-42\u00a0C\u2009&gt;\u2009T heterozygous relatives from both families had either no or extremely low levels of\n                    <jats:italic>MLH1<\/jats:italic>\n                    methylation within blood or saliva. Allelic expression from\n                    <jats:italic>MLH1<\/jats:italic>\n                    c.-42T was reduced to 70% relative to the wild-type allele in saliva from three heterozygotes. Three additional pedigrees were identified from the Colon Cancer Family Registry. Evaluation of combined multifactorial data from pooled informative index cases supports reclassification of this variant as \u201clikely pathogenic\u201d according to current ACMG\/AMP mismatch repair gene-specific guidelines, though with likely reduced penetrance and\/or modified phenotype. These findings highlight the clinical importance of identifying\n                    <jats:italic>MLH1<\/jats:italic>\n                    c.-42\u00a0C\u2009&gt;\u2009T to inform cancer risk management.\n                  <\/jats:p>","DOI":"10.1007\/s10689-025-00519-y","type":"journal-article","created":{"date-parts":[[2026,1,31]],"date-time":"2026-01-31T05:17:00Z","timestamp":1769836620000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Germline MLH1 c.-42\u00a0C\u2009&gt;\u2009T is a likely pathogenic variant predisposing to a reduced-penetrance\/modified Lynch syndrome phenotype featuring MLH1-methylated cancers"],"prefix":"10.1007","volume":"25","author":[{"given":"Daniel D.","family":"Buchanan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio","family":"Alvarez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Mahmood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Clendenning","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Georgeson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Como","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan G.","family":"Preston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharelle","family":"Joseland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimia","family":"Mohammadsaeedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Aguirre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis J.","family":"Hazelett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christophe","family":"Rosty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid M.","family":"Winship","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Finlay A.","family":"Macrae","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanya M.","family":"Dwarte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Nixon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan P.","family":"Hitchins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihoon E.","family":"Joo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"issue":"3","key":"519_CR1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/nrc3878","volume":"15","author":"HT Lynch","year":"2015","unstructured":"Lynch HT, Snyder CL, Shaw TG, Heinen CD, Hitchins MP (2015) Milestones of Lynch syndrome: 1895\u20132015. 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The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the University of Melbourne Human Research Ethics Committee (HREC#1750748) or the Cedars-Sinai Medical Center Institutional Review Board (#Pro00049624).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"17"}}