ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.865T>C (p.Phe289Leu) (rs771787834)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587850 SCV000571120 uncertain significance not provided 2016-07-26 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.865T>C at the cDNA level, p.Phe289Leu (F289L) 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 Phe289Leu 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 Phe289Leu 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 evidence, it is unclear whether PMS2 Phe289Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587850 SCV000697396 uncertain significance not provided 2016-03-11 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.865T>C variant affects a conserved nucleotide, resulting in amino acid change from Phe to Leu. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant was found in 1/120952 control chromosomes at a frequency of 0.0000083, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0001136). However, due to potential pseudogene interference, it is unknown if this variant call is in PMS2 or the pseudogene. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000819237 SCV000959886 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-09-18 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 289 of the PMS2 protein (p.Phe289Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs771787834, ExAC 0.002%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 421809). 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 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.
Ambry Genetics RCV001018145 SCV001179338 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-11 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001018145 SCV001354715 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-14 criteria provided, single submitter clinical testing

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