ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs876661158
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Total submissions: 4
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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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000527584 SCV000625693 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-06-06 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 267 of the PMS2 protein (p.Phe267Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234679). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV001027031 SCV001189527 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-22 criteria provided, single submitter clinical testing The p.F267L variant (also known as c.799T>C), located in coding exon 7 of the PMS2 gene, results from a T to C substitution at nucleotide position 799. The phenylalanine at codon 267 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800582 SCV002046996 uncertain significance not specified 2021-05-13 criteria provided, single submitter clinical testing

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