ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.292G>C (p.Gly98Arg) (rs267607725)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216356 SCV000279070 uncertain significance not provided 2015-09-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.292G>C at the cDNA level, p.Gly98Arg (G98R) at the protein level, and results in the change of a Glycine to an Arginine (GGC>CGC). This variant has been reported in one individual with either colorectal or urothelial cancer and in an individual meeting Amsterdam II criteria whose tumor showed microsatellite instability (MSI-H) but intact expression of the mismatch repair proteins by immunohistochemistry (IHC) (Bujalkova 2008, Kovac 2011). MLH1 Gly98Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly98Arg occurs at a position that is conserved across species and is located in the ATPase domain (Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as one of uncertain significance based on insufficient evidence (Thompson 2014). Based on currently available evidence, we consider MLH1 Gly98Arg to be a variant of uncertain significance.
Invitae RCV000693726 SCV000821607 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 98 of the MLH1 protein (p.Gly98Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individual affected with hereditary non-polyposis colorectal cancer or Lynch syndrome (PMID: 18772310, 21671081). ClinVar contains an entry for this variant (Variation ID: 90129). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. This variant disrupts the p.Gly98 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22290698, 185612205). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV001017525 SCV001178615 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Rarity in general population databases (dbsnp, esp, 1000 genomes);Structural Evidence

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