ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1744C>T (p.Leu582Phe) (rs63751713)

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
GeneDx RCV000480905 SCV000565161 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1744C>T at the cDNA level, p.Leu582Phe (L582F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has been reported in individuals with early onset colorectal cancer, whose tumor testing demonstrated microsatellite instability and loss of MLH1, and also loss of PMS2 when performed, on mismatch repair immunohistochemistry (IHC) (Hendriks 2003, van Puijenbroek 2008, van der Klift 2016). Functional assays demonstrate MLH1 Leu582Phe to have reduced mismatch repair activity compared to wild-type, while other assays show defective MLH1-PMS2 dimerization (Drost 2010, Andersen 2012). MLH1 Leu582Phe 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 Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu582Phe occurs at a position that is conserved across species and is located in the PMS2/MLH3/PMS1 interaction domain and region of interaction with EXO1 (Pang 1997, 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 Leu582Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000556108 SCV000625096 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-06-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 582 of the MLH1 protein (p.Leu582Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with colon cancer (PMID: 18415027, 12547705), it has also been reported in an individual with Lynch syndrome (PMID: 27435373) as co-occurring with a variant in PMS2 (p.Glu504Gln) (PMID: 27435373), and it has been reported in an individual with gastrointestinal cancer (PMID: 23760103). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89870). Experimental studies have shown that this missense change results in loss of mismatch repair activity and loss of interaction with PMS2 (PMID: 20020535, 22753075). In summary, while this variant has been reported to impact on MLH1 function, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781534 SCV000919640 uncertain significance not specified 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1744C>T (p.L582F) variant involves the alteration of a highly conserved nucleotide and 3/4 in silico tools predict a damaging outcome for this variant. The variant is located within the PMS2/MLH3/PMS1 interaction domain and the abrogated interactions between MLH1 and PMS2 partners in addition to the variant being deficient in an MMR complementation assay were confirmed by functional studies (Drost_2009; Andersen_2012). Tumors for carriers of this variant showed MSH-H and loss of MLH1-PMS2 staining. The variant is absent from the large control datasets of ExAC and gnomAD (121282 and 246040, chrs tested respectively). The variant was identified in several affected individuals (Hendriks_2003; van Puijenbroek_2008; van der Klift_2016). Although several clinical diagnostic laboratories/reputable databases cite the variant with a classification of VUS, the collective evidence points towards a deleterious effect. Taken together, the variant was classified as VUS-Possibly Pathogenic, until more data becomes available.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000480905 SCV001153848 likely pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480905 SCV001469797 likely pathogenic not provided 2020-04-22 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.

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.