ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.527A>G (p.Tyr176Cys) (rs757498880)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000579637 SCV000215726 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000470284 SCV000541614 uncertain significance PTEN hamartoma tumor syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 176 of the PTEN protein (p.Tyr176Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs757498880, ExAC 0.02%). This variant has been shown to arise de novo in an individual affected with severe mental retardation, autism and macrocephaly (PMID: 18759867), and has been reported in individuals affected with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome, collectively also known as PTEN hamartoma tumor syndrome (PHTS) (PMID: 21659347, 21194675). This variant is also known as c.530A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 185585). An experimental study has shown that this missense change results in partially reduced catalytic activity and slightly reduced thermostability of the PTEN protein in vitro (PMID: 25647146), although a different study has shown that this variant is comparable to wild-type PTEN protein in its phosphatase activity in a yeast-based assay (PMID: 21828076). In addition, an in vivo study has shown that this variant affects the regulation of excitatory and inhibitory interneuron ratios and soma size in mouse medial ganglionic eminence cells, but the clinical significance of this finding is uncertain (PMID: 25937288). 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.
GeneDx RCV000482161 SCV000568256 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing This variant is denoted PTEN c.527A>G at the cDNA level, p.Tyr176Cys (Y176C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). This variant was observed in a child with autism and a head circumference slightly greater than the 98th centile for his age; however, different cDNA nomenclature was cited as corresponding to this amino acid change and the possibility that this is a different variant cannot be excluded (Orrico 2009). This variant was also observed in at least one individual with features of Cowden syndrome (Pilarski 2011, Tan 2011). In one functional study, this variant displayed phosphatase activity similar to wild-type; however, in another study there was a decrease in catalytic efficacy and conformational stability (Rodriguez-Escudero 2011, Johnston 2015). In addition, in an in vivo study, this variant demonstrated functional deficits in interneuron development (Vogt 2015). PTEN Tyr176Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the phosphatase domain (Molinari 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PTEN Tyr176Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000579637 SCV000686292 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-08 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.