ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.381-1G>A (rs267607744)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480828 SCV000565144 pathogenic not provided 2017-09-11 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.381-1G>A or IVS4-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 4 of the MLH1 gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in association with Lynch syndrome (Guindalini 2015, Roth 2016). Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000205947 SCV000259785 likely pathogenic Hereditary nonpolyposis colon cancer 2018-11-01 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 4 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). This variant has been reported in multiple individuals affected with Lynch syndrome (PMID: 26248088). ClinVar contains an entry for this variant (Variation ID: 219740). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480828 SCV000601397 likely pathogenic not provided 2016-10-14 criteria provided, single submitter clinical testing

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