ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.677+1G>T (rs267607778)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075803 SCV000106818 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV001034678 SCV000543594 pathogenic Hereditary nonpolyposis colon cancer 2019-11-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 8 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 the literature in individuals affected with a MLH1-related disease (PMID: 12624141, 15342696, 17312306, 27601186, Invitae). This variant is also known as IVS8+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 90312). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). 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 RCV000480845 SCV000567308 pathogenic not provided 2015-07-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.677+1G>T or IVS8+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 8 of the MLH1 gene. The variant destroys a canonical splice donor 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 individuals with familial and/or early-onset colorectal cancer, including one individual whose colorectal tumor demonstrated microsatellite instability (Parc 2003, Domingo 2004, Lagerstedt Robinson 2007). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on their multifactorial likelihood analysis (Thompson 2014). Based on the current evidence, we consider MLH1 c.677+1G>T to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193208 SCV001361914 pathogenic Lynch syndrome 2019-04-24 criteria provided, single submitter clinical testing Variant summary: MLH1 c.677+1G>T 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. 4/5 computational tools predict a significant impact on normal splicing and abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250982 control chromosomes (gnomAD). The variant, c.677+1G>T, has been reported in the literature in individuals affected with Lynch Syndrome and early-onset colorectal cancer (Parc_2003, Domingo_2004, Tanskanen_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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