ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.487T>C (p.Phe163Leu) (rs587780060)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212843 SCV000149606 uncertain significance not specified 2017-04-03 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.487T>C at the cDNA level, p.Phe163Leu (F163L) 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 Phe163Leu 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 Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Phe163Leu occurs at a position that is conserved across species and is located in the ATPase domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether PMS2 Phe163Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115697 SCV000212838 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000227288 SCV000285136 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 163 of the PMS2 protein (p.Phe163Leu). 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). This variant has been observed in in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 127792). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Counsyl RCV000411957 SCV000489637 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2016-11-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515175 SCV000611424 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000115697 SCV000686209 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985911 SCV001134604 uncertain significance not provided 2018-11-01 criteria provided, single submitter clinical testing

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