ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.493G>A (p.Gly165Arg) (rs587782603)

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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 RCV000491530 SCV000580051 likely pathogenic Hereditary cancer-predisposing syndrome 2015-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
GeneDx RCV000522601 SCV000617324 pathogenic not provided 2017-08-16 criteria provided, single submitter clinical testing The G165R variant in the PTEN gene was observed in at least one individual with breast cancer, and in one individual undergoing clinical testing of the PTEN gene (Banneau et al., 2010; Pilarksi et al., 2011). Functional studies show that G165R significantly decreases PTEN phosphatase activity (Myers et al., 1997; Han et al., 2000). This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al., 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. This substitution occurs at a position that is conserved across species and is located in the phosphatase domain (Molinari et al., 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000690443 SCV000818127 uncertain significance PTEN hamartoma tumor syndrome 2018-03-16 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 165 of the PTEN protein (p.Gly165Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Cowden syndrome, and in one individual affected with either Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 20712882, 21194675, 21659347). ClinVar contains an entry for this variant (Variation ID: 428256). Experimental studies have shown that this missense change disrupts the phosphatase activity of the PTEN protein (PMID: 10866302, 9256433). 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.

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