ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1559-1G>C (rs267607837)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075254 SCV000106252 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000539690 SCV000625078 pathogenic Hereditary nonpolyposis colorectal neoplasms 2018-07-20 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 13 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals with suspected Lynch syndrome (PMID: 12624141, 15926618). This variant is also known as IVS13-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 89780). Different variants affecting this nucleotide (c.1559-1G>T, c.1559-1G>A) have been determined to be pathogenic (PMID: 8776590, 15849733). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants 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). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001012154 SCV001172575 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-29 criteria provided, single submitter clinical testing <span style="font-family:arial,helvetica,sans-serif">The c.1559-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 14 of the MLH1 gene. This alteration has been seen in multiple families at high risk for <span style="color:rgb(54, 43, 54)">hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (Parc Y et al. J. Med. Genet. 2003 Mar;40:208-13; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117:269-77).<span style="font-family:arial,helvetica,sans-serif"> This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice acceptor site, and is predicted to weaken the efficiency of the native splice acceptor site by ESEfinder; however, direct evidence is unavailable. 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 likely pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV001091800 SCV001248020 likely pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Color Health, Inc RCV001012154 SCV001345307 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-23 criteria provided, single submitter clinical testing

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