ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.678-2A>G (rs587779035)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075815 SCV000106829 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000569823 SCV000662117 pathogenic Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing The c.678-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 9 in the MLH1 gene. An in vitro splicing assay found that this mutation caused skipping of exon 9 which led to an out-of-frame transcript (Thompson BA et al. Hum. Mutat., 2013 Jan;34:200-9). 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.
Color Health, Inc RCV000569823 SCV000908612 likely pathogenic Hereditary cancer-predisposing syndrome 2020-06-03 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the MLH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae RCV001380125 SCV001578071 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-03-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 8 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with colorectal cancer (PMID: RQ1138090). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90324). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.

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