ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1990-1G>C (rs267607884)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Health, Inc RCV000772614 SCV000905795 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772614 SCV001174619 pathogenic Hereditary cancer-predisposing syndrome 2018-02-07 criteria provided, single submitter clinical testing The c.1990-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 18 of the MLH1 gene. <span style="background-color:initial">A similar alteration at the same nucleotide position, <span style="background-color:initial">c.1990-1G>A, has been reported in a family meeting Amsterdam criteria and was shown to cause exon skipping (<span style="background-color:initial">G<span style="background-color:initial">odino<span style="background-color:initial"> J et al. Hum. Mutat. 2001 Dec;18(6):549; Thompson BA et al. Hum. Mutat. 2013 Jan;34(1):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.
Invitae RCV001036557 SCV001199927 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 17 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 clinical features of Lynch syndrome (PMID: 15365996, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 628266). 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.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310199 SCV001499800 pathogenic Lynch syndrome I 2020-04-02 criteria provided, single submitter clinical testing

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