ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.589-1G>T

dbSNP: rs587779027
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075779 SCV000106789 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV001070764 SCV001236032 pathogenic Hereditary nonpolyposis colorectal neoplasms 2021-01-20 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individuals affected with Lynch syndrome (LS) or clinical features of LS (PMID: 12658575, 12067992, 15178966). This variant is also known as IVS7-1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 90290). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 7 of the MLH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816).
Sema4, Sema4 RCV002258789 SCV002528757 likely pathogenic Hereditary cancer-predisposing syndrome 2021-04-19 criteria provided, single submitter curation
Ambry Genetics RCV002258789 SCV002653611 pathogenic Hereditary cancer-predisposing syndrome 2020-10-15 criteria provided, single submitter clinical testing The c.589-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 8 of the MLH1 gene. This mutation, designated as IVS7-1G>T, has been reported in a family meeting Amsterdam criteria (Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics RCV002483124 SCV002792208 likely pathogenic Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2 2022-02-15 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003452754 SCV004190030 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-17 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].

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