ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2104-2A>T

dbSNP: rs267607889
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075540 SCV000106540 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics RCV002415543 SCV002724576 pathogenic Hereditary cancer-predisposing syndrome 2023-10-10 criteria provided, single submitter clinical testing The c.2104-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides before coding exon 19 of the MLH1 gene. This variant, described as an A to T transversion in the first base pair of the acceptor site, has been identified in a proband who met Amsterdam I criteria for Lynch syndrome (Buerstedde JM et al. J Med Genet. 1995 Nov;32(11):909-12; Heinimann K et al. Cancer. 1999 Jun 15;85(12):2512-8). This alteration was also reported in a colon tumor that showed high microsatellite instability and loss of heterozygosity (Bujalkova M et al. Clin Chem. 2008 Nov;54(11):1844-54). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition to the clinical data presented in the literature, 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.
Myriad Genetics, Inc. RCV003451106 SCV004187246 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-25 criteria provided, single submitter clinical testing This variant is considered likely 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.

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