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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