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Of the 3798 MLH1 germline variants collected in the ClinVar database, 38.7% (1469) were missense variants, of which 81.6% (1199) were classified as Variants of Uncertain Significance (VUS) due to the lack of functional evidence. Further determination of the impact of VUS on MLH1 function is important for the VUS carriers to take preventive action. We recently developed a protein structure-based method named \u201cDeep Learning-Ramachandran Plot-Molecular Dynamics Simulation (DL-RP-MDS)\u201d to evaluate the deleteriousness of MLH1 missense VUS. The method extracts protein structural information by using the Ramachandran plot-molecular dynamics simulation (RP-MDS) method, then combines the variation data with an unsupervised learning model composed of auto-encoder and neural network classifier to identify the variants causing significant change in protein structure. In this report, we applied the method to classify 447 MLH1 missense VUS. We predicted 126\/447 (28.2%) MLH1 missense VUS were deleterious. Our study demonstrates that DL-RP-MDS is able to classify the missense VUS based solely on their impact on protein structure.<\/jats:p>","DOI":"10.3390\/ijms25020850","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T07:50:48Z","timestamp":1704873048000},"page":"850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Classification of MLH1 Missense VUS Using Protein Structure-Based Deep Learning-Ramachandran Plot-Molecular Dynamics Simulations Method"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8119-3996","authenticated-orcid":false,"given":"Benjamin","family":"Tam","sequence":"first","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixin","family":"Qin","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojin","family":"Zhao","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3868-1967","authenticated-orcid":false,"given":"Siddharth","family":"Sinha","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0904-554X","authenticated-orcid":false,"given":"Chon Lok","family":"Lei","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2172-1320","authenticated-orcid":false,"given":"San Ming","family":"Wang","sequence":"additional","affiliation":[{"name":"Ministry of Education Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Cancer Centre, Faculty of Health Sciences, University of Macau, Macau SAR, China"},{"name":"Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e2022704118","DOI":"10.1073\/pnas.2022704118","article-title":"Molecular basis of the dual role of the Mlh1-Mlh3 endonuclease in MMR and in meiotic crossover formation","volume":"118","author":"Dai","year":"2021","journal-title":"Proc. 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