ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.117-2A>G (rs267607712)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000780423 SCV000920458 pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability > 0.99 (1.0)
Ambry Genetics RCV000132299 SCV000187384 pathogenic Hereditary cancer-predisposing syndrome 2018-11-28 criteria provided, single submitter clinical testing 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;Functionally-validated splicing mutation
Invitae RCV000200647 SCV000253784 pathogenic Hereditary nonpolyposis colon cancer 2017-03-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 1 of the MLH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic. This particular variant has been reported in the literature in individuals affected with Lynch syndrome and colon cancer (PMID: 25117503, 26248088, 15713769). This variant is also known as IVS01-2A>G in the literature. Experimental studies have shown that this variant causes a defect in mRNA splicing (PMID: 15713769, 24811117). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000478069 SCV000568561 pathogenic not provided 2017-03-06 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.117-2A>G or IVS1-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 1 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 mulitple individuals with colorectal cancer, including at least three with personal and family histories fulfilling clinical Lynch syndrome criteria (Casey 2005, Rosty 2014, Guindalini 2015, Pearlman 2016). Based on the current evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478069 SCV000601347 pathogenic not provided 2017-01-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780423 SCV000917666 pathogenic Lynch syndrome 2018-12-20 criteria provided, single submitter clinical testing Variant summary: MLH1 c.117-2A>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: Four predict the variant abolishes a 3' acceptor site. Three predict the variant strengthens a cryptic exonic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246232 control chromosomes (gnomAD). c.117-2A>G has been reported in the literature in multiple individuals affected with Lynch Syndrome and colorectal cancer (Espenschied_2017, Pearlman_2017, Guindalini_2015, Casey_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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