ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1559-2A>C

dbSNP: rs267607836
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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) RCV000075256 SCV000106254 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000524243 SCV000543640 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-07-29 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1559-2 nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12183410, 12373605, 21642682, 22322191, 22949379, 24278394). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Studies have shown that disruption of this splice site results in skipping of exon 14 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 89782). This variant is also known as "cagACT->caaACT at splice acceptor of exon 14". Disruption of this splice site has been observed in individual(s) with hereditary nonpolyposis colorectal cancer (PMID: 10200055, 24344984). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 13 of the MLH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Myriad Genetics, Inc. RCV003451034 SCV004186516 pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2023-07-20 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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