ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.1105G>A (p.Val369Ile) (rs587782224)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130915 SCV000185825 uncertain significance Hereditary cancer-predisposing syndrome 2013-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000486316 SCV000572714 uncertain significance not provided 2017-01-12 criteria provided, single submitter clinical testing This variant is denoted PTEN c.1105G>A at the cDNA level, p.Val369Ile (V369I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PTEN Val369Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. PTEN Val369Ile occurs at a position that is conserved across species and is located in the C-terminal 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 Val369Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000556721 SCV000645546 uncertain significance PTEN hamartoma tumor syndrome 2017-02-24 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 369 of the PTEN protein (p.Val369Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PTEN-related disease. ClinVar contains an entry for this variant (Variation ID: 142088). 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. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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