ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1690C>T (p.Leu564Phe) (rs786202693)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165630 SCV000216366 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes) ,In silico models in agreement (benign)
Color RCV000165630 SCV000911977 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-05 criteria provided, single submitter clinical testing
Counsyl RCV000662425 SCV000784876 uncertain significance Lynch syndrome II 2017-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000478918 SCV000570244 uncertain significance not provided 2016-05-10 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1690C>T at the cDNA level, p.Leu564Phe (L564F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu564Phe 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 Leu564Phe occurs at a position that is conserved across species and is located in the domain of interaction with PMS2/MLH3/PMS1 as well as a region of interaction with EXO1 (Pang 1997, Raevaara 2005, 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 Leu564Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229336 SCV000284026 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 564 of the MLH1 protein (p.Leu564Phe). 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 not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 186100). 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: "Benign"; 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.

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