ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1475C>T (p.Ala492Val) (rs1064794826)

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 RCV000483640 SCV000570028 uncertain significance not provided 2016-04-18 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1475C>T at the cDNA level, p.Ala492Val (A492V) at the protein level, and results in the change of an Alanine to a Valine (GCA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ala492Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MLH1 Ala492Val occurs at a position that is conserved across species and is located within the region of interaction with PMS2/MLH3/PMS1 and EXO1 (Raevaara 2005, Hardt 2011, Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Ala492Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572658 SCV000669565 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000690155 SCV000817833 uncertain significance Hereditary nonpolyposis colon cancer 2018-02-16 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 492 of the MLH1 protein (p.Ala492Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 420973). 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. 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.