ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.145G>A (p.Val49Met)

gnomAD frequency: 0.00002  dbSNP: rs760185532
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985776 SCV001134291 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing
GeneDx RCV000985776 SCV001990434 uncertain significance not provided 2019-07-18 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies are inconclusive: Reduction in mismatch repair (MMR) function (Ellison 2004); This variant is associated with the following publications: (PMID: 15475387)
Invitae RCV001858627 SCV002251804 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-02-04 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 49 of the MLH1 protein (p.Val49Met). This variant is present in population databases (rs760185532, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 801201). 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. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387). 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.

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.