ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.454-2A>G

dbSNP: rs267607753
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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) RCV000075721 SCV000106732 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000218165 SCV000277157 pathogenic Hereditary cancer-predisposing syndrome 2022-07-14 criteria provided, single submitter clinical testing The c.454-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 6 in the MLH1 gene. RNA studies have demonstrated that this alteration results in coding exon 6 skipping (Auclair J et al. Hum. Mutat. 2006 Feb; 27(2):145-54; Ambry internal data). In addition to the report 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001854302 SCV002245940 pathogenic Hereditary nonpolyposis colorectal neoplasms 2024-03-30 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 7584997, 8940269, 10829038, 14574010, 23544471, 27601186; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90232). Studies have shown that disruption of this splice site results in skipping of exon 6 and introduces a premature termination codon (PMID: 7584997, 15235038, 16395668). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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