ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.791-2A>G (rs267607794)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075863 SCV000106880 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
GeneDx RCV000212525 SCV000149395 pathogenic not provided 2017-11-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.791-2A>G or IVS9-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 9 of the MLH1 gene. The 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 the literature in association with Lynch syndrome with at least one tumor showing loss of MLH1 and PMS2 expression (Samowitz 2001, Sjursen 2010, Bonadona 2011). Based on the currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000115486 SCV000213526 pathogenic Hereditary cancer-predisposing syndrome 2018-04-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Invitae RCV000543128 SCV000625196 likely pathogenic Hereditary nonpolyposis colon cancer 2018-12-17 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 9 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 individuals and families affected with Lynch syndrome (PMID: 12624141, 20587412, 11606497, 21642682). This variant is also known as IVS9-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 90372). 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.
Color RCV000115486 SCV000908614 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing

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