ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1628A>G (p.His543Arg) (rs730881742)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160537 SCV000217067 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000160537 SCV000908637 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-09 criteria provided, single submitter clinical testing
Counsyl RCV000409504 SCV000489326 uncertain significance Lynch syndrome II 2016-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000212541 SCV000211110 uncertain significance not provided 2018-09-26 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1628A>G at the cDNA level, p.His543Arg (H543R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 His543Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the EXO1 and PMS2/MLH3/PMS1 interaction region (Raevaara 2005, Kansikas, 2011, Andersen 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 His543Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000206589 SCV000260515 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 543 of the MLH1 protein (p.His543Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs730881742, ExAC 0.004%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 182526). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.