ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1271T>C (p.Phe424Ser) (rs876661186)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767177 SCV000279745 uncertain significance not provided 2015-12-31 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1271T>C at the cDNA level, p.Phe424Ser (F424S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Phe424Ser 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 Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Phe424Ser occurs at a position that is conserved across species and is not located in a known functional domain. 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 Phe424Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218654 SCV000601813 uncertain significance not specified 2017-04-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573020 SCV000676164 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-10 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Mendelics RCV000708983 SCV000838179 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV001048582 SCV001212595 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 424 of the PMS2 protein (p.Phe424Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 234733). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; 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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