ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1460G>A (p.Arg487Gln) (rs587778917)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000218037 SCV000275866 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
GeneDx RCV000480533 SCV000571659 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1460G>A at the cDNA level, p.Arg487Gln (R487Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg487Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Arg487Gln is located in the region of interaction with EXO1 (Andersen 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Arg487Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000630048 SCV000751004 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 487 of the MLH1 protein (p.Arg487Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587778917, ExAC 0.03%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 89745). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color RCV000218037 SCV000903938 likely benign Hereditary cancer-predisposing syndrome 2016-10-16 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.