ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.799T>C (p.Phe267Leu) (rs876661158)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219045 SCV000279682 uncertain significance not provided 2015-12-15 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.799T>C at the cDNA level, p.Phe267Leu (F267L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Phe267Leu 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 Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Phe267Leu occurs at a position that is not conserved and is located in the ATPase domain (Fukui 2011). 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 PMS2 Phe267Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000527584 SCV000625693 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2017-03-15 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 267 of the PMS2 protein (p.Phe267Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234679). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001027031 SCV001189527 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-17 criteria provided, single submitter clinical testing Insufficient evidence

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