ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1876T>C (p.Phe626Leu) (rs377241633)

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 RCV000214440 SCV000274895 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000216958 SCV000279349 uncertain significance not provided 2017-08-15 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1876T>C at the cDNA level, p.Phe626Leu (F626L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>CTC). This variant has been reported to have co-occurred with two pathogenic variants either in MLH1 or in another Mismatch Repair gene (Coffee 2015). MLH1 Phe626Leu was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. MLH1 Phe626Leu occurs at a position that is conserved across species and is located in the region responsible for interaction with EXO1 (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Phe626Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000462112 SCV000543608 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 626 of the MLH1 protein (p.Phe626Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs377241633, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 231139). 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: "Deleterious"; PolyPhen-2: "Probably 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.
Mendelics RCV000708930 SCV000838027 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000214440 SCV000903142 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-18 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.