Submissions for variant NM_000314.8(PTEN):c.475A>G (p.Arg159Gly)

dbSNP: rs786202688

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165624	SCV000216360	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-05	criteria provided, single submitter	clinical testing	The p.R159G variant (also known as c.475A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 475. The arginine at codon 159 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in individuals with features of Cowden syndrome (Tan MH et al. Am J Hum Genet, 2011 Jan;88:42-56; Busch RM et al. Transl Psychiatry, 2019 Oct;9:253). Yeast studies have indicated that this alteration compromises PTEN protein function (Andrés-Pons A, Cancer Res. 2007 Oct; 67(20):9731-9). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). However, this variant demonstrated wild type-like intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). Based on the crystal structure for the PTEN protein, Arg159 stabilizes the conformation of the catalytic p-loop and the glycine substitution is expected to disrupt this interaction (Lee JO, Cell 1999 Oct; 99(3):323-34; Rodríguez-Escudero I, Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000760049	SCV000889803	likely pathogenic	not provided	2017-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193513	SCV001362399	likely pathogenic	Cowden syndrome	2019-12-05	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.475A>G (p.Arg159Gly) results in a non-conservative amino acid change located in the phosphatase domain (IPR029023) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250998 control chromosomes (gnomAD). c.475A>G has been reported in the literature in at least one individual affected with Cowden Syndrome (CS) or CS-like phenotype (Tan_2011). These data do not allow clear conclusions about variant significance. One publication reported experimental evidence and demonstrated that the variant protein expressed in mammalian cells resulted in increased levels of Akt1 phosphorylation (Andres-Pons_2007). In addition, another variant affecting the same amino acid (R159T) was reported to be found in a patient affected with CS or CS-like phenotype (HGMD, Tan_2011), further supporting a functional role for the affected residue. One ClinVar submitter (evaluation after 2014) cited the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515152	SCV003439628	pathogenic	PTEN hamartoma tumor syndrome	2024-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 159 of the PTEN protein (p.Arg159Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cowden syndrome (PMID: 21194675, 31594918; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 186094). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 17942903). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000760049	SCV003837300	likely pathogenic	not provided	2022-09-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24475377, 21194675, 29785012, 10555148, 21828076, 17942903, 31594918, 29706350)