ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.885-2A>G (rs267607805)

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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) RCV000075914 SCV000106934 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000132040 SCV000187099 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-09 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Rarity in general population databases (dbsnp, esp, 1000 genomes);Other data supporting pathogenic classification
Invitae RCV000627716 SCV000284080 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-05-09 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 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 an individual with Lynch syndrome (PMID: 11208710), and as de novo in an individual affected with a Lynch syndrome-associated cancer (Invitae). This variant is also referred to as IVS10-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 90421). 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.
GeneDx RCV000481722 SCV000571393 likely pathogenic not provided 2016-08-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.885-2A>G or IVS10-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 10 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 at least one individual with a colorectal tumor demonstrating microsatellite instability (Terdiman 2001) and is classified by the International Society for Gastrointestinal Tumours Incorporated (InSiGHT) as likely pathogenic (Thompson 2014). Based on the currently available information, we consider MLH1 c.885-2A>G to be a likely pathogenic variant.
Color RCV000132040 SCV000908615 likely pathogenic Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing

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