ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.116+5G>C (rs267607710)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000776333 SCV000911687 pathogenic Hereditary cancer-predisposing syndrome 2017-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000413453 SCV000490614 pathogenic not provided 2019-05-02 criteria provided, single submitter clinical testing The guanine (G) nucleotide that is altered at the +5position is important for splicing and is conserved across species. Multiple in silico models predict this variant todamage or destroy the nearby natural splice donor site and to possibly cause abnormal gene splicing which was confirmed in multiple functional studies demonstrating that it destroys the natural splice donor site and introduces a 227base pair intronic insertion resulting in a frameshift (Arnold 2009, Naruse 2009). This variant was observed tosegregate with disease in multiple families with Lynch syndrome (Casey 2005, Thodi 2010, Thompson 2013). Tumorsfrom several of these individuals demonstrated microsatellite instability and absence of MLH1 protein on mismatchrepair immunohistochemistry (Casey 2005, Arnold 2009). This variant was not observed in large population cohorts(Lek 2016).
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075129 SCV000106120 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration predicted to produce truncated protein: full inactivation of variant allele. Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000694368 SCV000822810 pathogenic Hereditary nonpolyposis colon cancer 2018-04-06 criteria provided, single submitter clinical testing This sequence change falls in intron 1 of the MLH1 gene. It does not directly change the encoded amino acid sequence of the MLH1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several families affected with hereditary non polyposis colorectal cancer (HNPCC) (PMID: 15713769, 22949379, 19685281, 19267393, 20937110), and reported to segregate with disease in one family (PMID: 19267393). This variant is also known as c.IVS1 + 5G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 89658). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies using a conversion assay, minigene assay, and patient-derived lymphoblastoid cells have shown that this missense change activates a cryptic splice site, resulting in the retention of 227 nucleotides of intron 1, causing a downstream frameshift and subsequent premature stop codon (PMID: 15713769, 19685281, 19267393). Additionally, this variant has been determined to have a high probability of being pathogenic based on a multifactorial likelihood algorithm that used genetic, functional and in silico data (PMID: 22949379). For these reasons, this variant has been classified as Pathogenic.

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