ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.539T>G (p.Val180Gly) (rs63750102)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131749 SCV000186791 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneDx RCV000212519 SCV000211089 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.539T>G at the cDNA level, p.Val180Gly (V180G) at the protein level, and results in the change of a Valine to a Glycine (GTT>GGT). This variant was observed in at least one family with suspected hereditary colon cancer and an individual with endometrial cancer whose tumor showed absence of MLH1 via immunohistochemistry and low microsatellite instability (Nilbert 2009, Berends 2003). In addition, this variant was observed in an individual with glioblastoma who also harbored a disease-causing MSH2 variant (Therkildsen 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies MLH1 Val180Gly as uncertain based on insufficient evidence for classification (Thompson 2014). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Val180Gly is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Val180Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000524305 SCV000284065 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces valine with glycine at codon 180 of the MLH1 protein (p.Val180Gly). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glycine. This variant is present in population databases (rs63750102, ExAC 0.006%). This variant has been reported in individuals affected with Lynch syndrome (PMID: 18566915, 25648859), and one individual affected with endometrial cancer (PMID: 14645426). ClinVar contains an entry for this variant (Variation ID: 90257). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000411648 SCV000489405 uncertain significance Lynch syndrome II 2016-09-29 criteria provided, single submitter clinical testing
Color RCV000131749 SCV000684838 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212519 SCV001134315 uncertain significance not provided 2018-12-17 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212519 SCV001153835 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing

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