ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.922C>T (p.Arg308Cys) (rs1064794436)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480358 SCV000569177 uncertain significance not provided 2016-09-22 criteria provided, single submitter clinical testing This variant is denoted PTEN c.922C>T at the cDNA level, p.Arg308Cys (R308C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in melanoma and glioblastoma tumors (Fiano 2004, Abdel-Rahman 2006). PTEN Arg308Cys 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 Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Arg308Cys occurs at a position that is conserved in mammals and is located in the C2 domain (Wang 2008). 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 PTEN Arg308Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000526594 SCV000645632 uncertain significance PTEN hamartoma tumor syndrome 2018-09-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 308 of the PTEN protein (p.Arg308Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 420367). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on PTEN function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000561633 SCV000663586 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000561633 SCV000905825 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing

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