ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.589-2A>G (rs267607767)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160526 SCV000212755 pathogenic Hereditary cancer-predisposing syndrome 2017-08-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s),Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color RCV000160526 SCV000905465 pathogenic Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing
Counsyl RCV000576331 SCV000677753 pathogenic Lynch syndrome II 2016-12-13 criteria provided, single submitter clinical testing
GeneDx RCV000212522 SCV000211093 pathogenic not provided 2018-06-21 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.589-2A>G or IVS7-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 7 of the MLH1 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing. RT-PCR analysis has shown MLH1 c.589-2A>G results in reduced mRNA expression levels suggesting an abnormal protein product is generated that is subject to nonsense-mediated mRNA decay (Casey 2005), and another in vitro study confirmed these results by demonstrating that this variant results in the use of a cryptic splice site and causes a frameshift (Arnold 2009). This variant has been reported in association with Lynch syndrome (Luce 1995, Syngal 1999, Thompson 2013). This variant is also described as a common pathogenic variant in individuals with Lynch syndrome in the United States (Tomsic 2012). Based on the current evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000075780 SCV000917650 pathogenic Lynch syndrome 2018-04-17 criteria provided, single submitter clinical testing Variant summary: MLH1 c.589-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Thompson_2013). The variant was absent in 246208 control chromosomes (gnomAD). The variant, c.589-2A>G has been reported in the literature in individuals affected with Lynch Syndrome (Syngal_1999, Susswein_2016, Tannergard_1995, Capozzi_1999). These data indicate that the variant is likely to be associated with disease. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075780 SCV000106790 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberrations: full inactivation of variant allele. Multifactorial likelihood analysis posterior probability >0.99.
Invitae RCV000524306 SCV000219008 pathogenic Hereditary nonpolyposis colon cancer 2018-12-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 7 of the MLH1 gene. It is expected to disrupt mRNA 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 several individuals and families affected with Lynch syndrome, and is considered to be a founder mutation in the United States (PMID: 7557107, 10422993, 21671475). ClinVar contains an entry for this variant (Variation ID: 90291). This variant falls in intron 7 at a highly conserved splice acceptor site that is predicted to result in either skipping of exon 8, or using a cryptic splice acceptor site that results in an out-of-frame protein (PMID: 22949379, 19267393). Experimental studies using a PCR-based in vitro transcription and translation assay demonstrate exon 8 skipping in mRNA from patient lymphoblast cells (PMID: 7557107). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212522 SCV000601404 pathogenic not provided 2016-08-12 criteria provided, single submitter clinical testing

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