ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.790+1G>A (rs267607789)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075847 SCV000106862 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration interrupting protein function: full inactivation of variant allele
GeneDx RCV000214767 SCV000279403 pathogenic not provided 2018-11-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.790+1G>A or IVS9+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 9 of the MLH1 gene. Splicing assays have demonstrated that this variant results in skipping of exons 9 and 10 (Casey 2005, Auclair 2006). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. MLH1 c.790+1G>A has been reported in many individuals with a personal and family history of Lynch syndrome-associated cancers with tumors demonstrating microsatellite instability and loss of MLH1 and/or PMS2 expression by immunohistochemistry (Cunningham 2001, Alvarez 2010, Thodi 2010, Loizidou 2014, Rosty 2016). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). We consider MLH1 c.790+1G>A to be pathogenic.
Invitae RCV000524316 SCV000284075 pathogenic Hereditary nonpolyposis colon cancer 2019-12-24 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 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 individuals with Lynch syndrome and colorectal cancer (PMID: 20937110, 17054581, 15849733, 11524701). This variant is also known as IVS9+1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 90356). Experimental studies using patient-derived RNA has shown that this variant causes significant skipping of exons 9 and 10 (PMID: 16395668), at a level far greater than the low-level alternate splicing reported in normal cells (PMID: 7728749, 9490293). This alternate splicing results in the loss of amino acids 227-295 in the MLH1 protein, which has been shown functionally to render MLH1 defective in mismatch repair activity (PMID: 11781295). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075847 SCV000592374 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214767 SCV000601410 pathogenic not provided 2016-12-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562275 SCV000664831 pathogenic Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Integrated Genetics/Laboratory Corporation of America RCV000075847 SCV000696180 pathogenic Lynch syndrome 2016-11-15 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.790+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant ablishes the 5' splicing donor site, which was confirmed by an in vitro study (Auclair_2006). This variant has been found in numerous LS patients and is absent in 115338 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Color RCV000562275 SCV000905468 pathogenic Hereditary cancer-predisposing syndrome 2018-07-03 criteria provided, single submitter clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249934 SCV001423876 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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