ArticleHuman mutation2015
Lynch syndrome associated with two MLH1 promoter variants and allelic imbalance of MLH1 expression.
Article in Human mutation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- Tumor microenvironment-aware, single-transcriptome prediction of microsatellite instability in colorectal cancer using meta-analysis.Scientific reports · 2022Pooled it
- Lynch syndrome withOpen life sciences · 2026Article
- HeterozygousJournal of medical genetics · 2025Article
- Regional-specific calibration enables application of computational evidence for clinical classification of 5' cis-regulatory variants in Mendelian disease.American journal of human genetics · 2024Article
- Whole exome sequencing identifies MAP3K1, MSH2, and MLH1 as potential cancer-predisposing genes in familial early-onset colorectal cancer.The Kaohsiung journal of medical sciences · 2023Article
- Article
- Identifying primary and secondary MLH1 epimutation carriers displaying low-level constitutional MLH1 methylation using droplet digital PCR and genome-wide DNA methylation profiling of colorectal cancers.Clinical epigenetics · 2023Article
- Germline variants associated with breast cancer in Khakass women of North Asia.Molecular biology reports · 2023Article
- Incomplete Penetrance and Variable Expressivity: From Clinical Studies to Population Cohorts.Frontiers in genetics · 2022Review
- Alterations of DNA damage repair in cancer: from mechanisms to applications.Annals of translational medicine · 2020Review
- Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients.Scientific reports · 2019Article
- Full-length transcript amplification and sequencing as universal method to test mRNA integrity and biallelic expression in mismatch repair genes.European journal of human genetics : EJHG · 2019Article
- Co-occurrence of breast cancer and neuroendocrine tumours: New genetic insights beyond Multiple Endocrine Neoplasia syndromes.Endocrinology, diabetes & metabolism · 2019Article
- Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation.Cancer medicine · 2018Article
- A NovelBioMed research international · 2018Article
- The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery.Cellular oncology (Dordrecht, Netherlands) · 2016Review
- Family-Specific Variants and the Limits of Human Genetics.Trends in molecular medicine · 2016Review
- The search for cis-regulatory driver mutations in cancer genomes.Oncotarget · 2015Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Lynch syndrome is a hereditary cancer syndrome caused by a constitutional mutation in one of the mismatch repair genes. The implementation of predictive testing and targeted preventative surveillance is hindered by the frequent finding of sequence variants of uncertain significance in these genes. We aimed to determine the pathogenicity of previously reported variants (c.-28A>G and c.-7C>T) within the MLH1 5'untranslated region (UTR) in two individuals from unrelated suspected Lynch syndrome families. We investigated whether these variants were associated with other pathogenic alterations using targeted high-throughput sequencing of the MLH1 locus. We also determined their relationship to gene expression and epigenetic alterations at the promoter. Sequencing revealed that the c.-28A>G and c.-7C>T variants were the only potentially pathogenic alterations within the MLH1 gene. In both individuals, the levels of transcription from the variant allele were reduced to 50% compared with the wild-type allele. Partial loss of expression occurred in the absence of constitutional epigenetic alterations within the MLH1 promoter. We propose that these variants may be pathogenic due to constitutional partial loss of MLH1 expression, and that this may be associated with intermediate penetrance of a Lynch syndrome phenotype. Our findings provide further evidence of the potential importance of noncoding variants in the MLH1 5'UTR in the pathogenesis of Lynch syndrome.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.