ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1038+1G>T

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Myriad Genetics, Inc. RCV003450331 SCV004187168 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-19 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.
Ambry Genetics RCV004636742 SCV005134150 pathogenic Hereditary cancer-predisposing syndrome 2024-04-15 criteria provided, single submitter clinical testing The c.1038+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 11 of the MLH1 gene. This variant has been detected in a Chilean individual meeting Amsterdam criteria who was diagnosed with MSI-H colorectal cancer exhibiting loss of MLH1 on immunohistochemistry (Wielandt AM et al. Rev Med Chil, 2012 Sep;140:1132-9; Rossi BM et al. BMC Cancer, 2017 Sep;17:623). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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