ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1490G>A (p.Arg497Gln) (rs754554026)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214903 SCV000279283 uncertain significance not provided 2018-09-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1490G>A at the cDNA level, p.Arg497Gln (R497Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant.. MLH1 Arg497Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Arg497Gln is located within the region of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In silico analysis, including protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Arg497Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000462302 SCV000543565 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 497 of the MLH1 protein (p.Arg497Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs754554026, ExAC 0.02%). This variant has not been reported in the literature in individuals with a MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 234466). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on MLH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000774707 SCV000908632 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-04 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.