ClinVar Miner

Submissions for variant NM_000314.7(PTEN):c.386G>A (p.Gly129Glu) (rs121909218)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413815 SCV000490751 pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted PTEN c.386G>A at the cDNA level, p.Gly129Glu (G129E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has been reported in multiple individuals with Cowden syndrome (Liaw 1997, Ngeow 2013, Chen 2016). Functional studies have shown PTEN Gly129Glu to lack lipid phosphatase activity and the ability to inhibit the PI-3K pathway as well as wild type (Leslie 2000, Rodriguez-Escudero 2011, He 2012). PTEN Gly129Glu was not observed in large population cohorts (Lek 2016). This variant is located in the phosphatase core domain and ATP binding motifs (Lee 1999, Lobo 2009, Molinari 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Herman Laboratory,Nationwide Children's Hospital RCV000490577 SCV000579270 pathogenic PTEN hamartoma tumor syndrome 2017-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV001021326 SCV001182928 pathogenic Hereditary cancer-predisposing syndrome 2018-05-11 criteria provided, single submitter clinical testing The p.G129E pathogenic mutation (also known as c.386G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 386. The glycine at codon 129 is replaced by glutamic acid, an amino acid with similar properties. This mutation has been reported in multiple Cowden syndrome and Cowden syndrome-like families (Liaw D et al. Nat. Genet. 1997 May; 16(1):64-7; Ngeow J et al. Gastroenterology 2013 Jun; 144(7):1402-9, 1409.e1-5; Pilarski R et al. J. Med. Genet. 2011 Aug;48(8):505-12). This mutation is located in the P-catalytic loop of the PTEN protein and has been shown to result in a fully inactive protein by in vivo functional analysis using a heterologous yeast reconstitution system (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). Multiple functional studies have also shown that this mutation leads to loss of lipid phosphatase activity and compromised dephosphorylation of active AKT, both of which are crucial to its tumor suppressor function (He X et al. J. Clin. Endocrinol. Metab. 2012 Nov; 97(11):E2179-87; Kandasamy K et al. Cancer Res. 2002 Sep; 62(17):4929-37; Ramaswamy S et al. Proc. Natl. Acad. Sci. U.S.A. 1999 Mar; 96(5):2110-5; Leslie NR et al. Biochem. J. 2000 Mar;346 Pt 3:827-33). Based on the available evidence, this variant is classified as a pathogenic mutation.
OMIM RCV000008255 SCV000028462 pathogenic Cowden syndrome 1 1999-03-02 no assertion criteria provided literature only

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