Submissions for variant NM_000314.8(PTEN):c.385G>A (p.Gly129Arg)

dbSNP: rs786204929

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000169874	SCV000222203	pathogenic	not provided	2019-09-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: decreased phosphatase activity (Furnari 1998, Spinelli 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 29142193, 28497778, 9823298, 25527629, 11274365, 15659546, 15988030, 25714556, 27481051, 22469695, 31085179, 33509259)
Ambry Genetics	RCV000570808	SCV000663579	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-14	criteria provided, single submitter	clinical testing	The p.G129R variant (also known as c.385G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 385. The glycine at codon 129 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in an individual with features of PTEN hamaratoma tumor syndrome (PHTS), including Lhermitte-Duclos disease and macrocephaly (Elia M et al. Brain Dev., 2012 Nov;34:873-6). Functional analyses of p.G129R have demonstrated PTEN protein stability similar to wild-type; however, it demonstrated a complete inability of the G129R mutated protein to suppress AKT signaling, a key role of PTEN (Spinelli L et al. J. Med. Genet., 2015 Feb;52:128-34). In addition, two mutations at the same codon, p.G129E and p.G129V have been detected in individuals with features of PHTS (Liaw D et al. Nat. Genet. 1997 May;16:64-7; Pilarski R et al. J. Med. Genet. 2011 Aug;48:505-12; Ngeow J et al. Gastroenterology. 2013 Jun; 144(7):1402-9, 1409.e1-5). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mendelics	RCV000988419	SCV001138132	likely pathogenic	PTEN hamartoma tumor syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000988419	SCV002233147	pathogenic	PTEN hamartoma tumor syndrome	2022-06-20	criteria provided, single submitter	clinical testing	This variant disrupts the p.Gly129 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21659347, 30327747). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 9256433, 17928923, 25527629). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 189484). This missense change has been observed in individual(s) with Cowden syndrome (PMID: 22469695). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine with arginine at codon 129 of the PTEN protein (p.Gly129Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine.
Myriad Genetics, Inc.	RCV003454441	SCV004188729	likely pathogenic	Cowden syndrome 1	2023-09-27	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 25527629]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22469695, 24766807].