ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1693T>G (p.Leu565Val) (rs786202870)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165917 SCV000216672 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000480451 SCV000565416 uncertain significance not provided 2014-08-01 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1693T>G at the cDNA level, p.Leu565Val (L565V) at the protein level, and results in the change of a Leucine to a Valine (TTG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Leu565Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. PMS2 Leu565Val occurs at a position that is variable across species and is not located in a functional domain (Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Leu565Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000531904 SCV000625552 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-12 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 565 of the PMS2 protein (p.Leu565Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine 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 a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 186338). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000415672 SCV000493781 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2015-08-13 no assertion criteria provided clinical testing

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