ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.-33T>G

gnomAD frequency: 0.00003  dbSNP: rs201247839
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217621 SCV000279065 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.-33T>G, and describes a nucleotide substitution 33 base pairs upstream of the MLH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is AGCA[T/G]CTAG. MLH1 c.-33T>G was identified along with a pathogenic MSH2 variant in an individual with an MSI-high colorectal cancer with absent expression of the MSH2 and MSH6 proteins (Hampel 2008). Of note, constitutional epigenetic silencing of MLH1 has been suggested as an alternate mechanism responsible for Lynch syndrome, and variants located within the MLH1 5' UTR have been shown to result in allele specific promoter methylation and subsequent transcriptional silencing (Hitchins 2009, Ward 2013). MLH1 c.-33T>G was not observed at a significant allele frequency in large population cohorts (Lek 2016). The thymine (T) nucleotide that is altered is not conserved. Based on currently available evidence, we consider MLH1 c.-33T>G to be a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences RCV003891797 SCV000805936 uncertain significance MLH1-related condition 2023-12-26 criteria provided, single submitter clinical testing The MLH1 c.-33T>G variant is located in the 5' untranslated region. This variant has been reported as a variant of uncertain significance in a patient with Lynch syndrome in a screen for causal MLH1 promoter and cis regulatory elements (Morak et al. 2018. PubMed ID: 29472279). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD, which may be too common to be a primary cause of disease. In ClinVar, it is interpreted as uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/234367/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Invitae RCV001455878 SCV001659645 likely benign Hereditary nonpolyposis colorectal neoplasms 2022-03-26 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV002256127 SCV002528739 uncertain significance Hereditary cancer-predisposing syndrome 2022-01-19 criteria provided, single submitter curation

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