ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1559-2A>C (rs267607836)

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Total submissions: 2
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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 2017-01-25 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 mRNA splicing and likely results in an absent or disrupted protein product. This sequence change has been reported in individuals and families with hereditary nonpolyposis colorectal cancer (PMID: 10200055, 24344984). This variant is also known as "cagACT->caaACT at splice acceptor of exon 14" in the literature Two different variants affecting this nucleotide (c.1559-2A>G and c.1559-2A>T) have been reported in individuals and families affected with Lynch syndrome (PMID: 12183410, 12373605, 21642682, 24278394, 22322191, 22949379). Experimental results also show that both c.1559-2A>G and c.1559-2A>T result in aberrant transcripts with skipping of exon 14 and/or exon 14 and 15 (PMID: 12183410, 22949379), indicating that this nucleotide is crucial for normal RNA splicing. For these reasons, this variant has been classified as Pathogenic.

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