ArticleMolecular genetics & genomic medicine2024
Reclassification of Two MLH1 Variants of Uncertain Significance Utilizing Clinical and Functional Data.
Article in Molecular genetics & genomic medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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2 citing papers in PubMed.
- Interactions between rare variants in DNA repair genes and cardiometabolic risk explain more variability in cognitive function.GeroScience · 2026Article
- Quality and Safety Imperatives in the Identification and Management of Hereditary Cancer Syndromes.Seminars in oncology nursing · 2026Review
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Authors and funding
16 authors.
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Abstract
backgroundPathogenic 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 MLH1 gene, c.696_698del, p.(Cys233del) and c.1919C > G, p.(Pro640Arg), in Danish families with numerous occurrences of CRC.
methodsTo reclassify the variants we collected clinical data, initiated tumor and co-segregation analysis, and performed RNA splicing analysis, subcellular localization, and protein stability studies.
resultsThe 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 > G, p.(Pro640Arg) variant showed decreased expression in localization studies and decreased protein stability. These results suggest both variants disrupt DNA mismatch repair.
conclusionBy applying all collected data and functional results we propose to reclassify the c.696_698del, p.(Cys233del) and the c.1919C > G, p.(Pro640Arg) variants as likely pathogenic (class 4) using MMR gene-specific ACMG/AMP guidelines. Consequently, the two MLH1 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.
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