Submissions for variant NM_000314.8(PTEN):c.510T>G (p.Ser170Arg)

dbSNP: rs121909221

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023564	SCV001185463	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-30	criteria provided, single submitter	clinical testing	The p.S170R pathogenic mutation (also known as c.510T>G), located in coding exon 6 of the PTEN gene, results from a T to G substitution at nucleotide position 510. The serine at codon 170 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in individuals suspected of having PTEN hamartoma tumor syndrome (PHTS) (Banneau G et al. Breast Cancer Res., 2010 Aug;12:R63; Ambry internal data). It was also seen in a proband with Bannayan-Riley-Ruvalcaba syndrome, as well as in their affected family members (Ghusayni R et al. 2018 Epileptic Disord. 2018 Feb;20(1):30-34). Another alteration (c.510T>A) with the same amino acid change (p.S170R) was reported in individuals who met clinical diagnostic criteria for PHTS and was reported to segregate with disease in three different families (Marsh DJ et al. Nat. Genet., 1997 Aug;16:333-4; de Leon MP et al. Dig Liver Dis, 2013 Jan;45:75-8; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Crucianelli F et al. Epigenetics, 2014 Oct;9:1431-8). The phosphatase activity of p.S170R was shown to be significantly reduced compared to wild type PTEN in several studies (Myers MP et al. Proc. Natl. Acad. Sci. U.S.A., 1997 Aug;94:9052-7; Han SY et al. Cancer Res., 2000 Jun;60:3147-5; Andrés-Pons A et al. Cancer Res., 2007 Oct;67:9731-9; Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lee CU et al. Angew. Chem. Int. Ed. Engl., 2015 Nov;54:13796-800). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003455124	SCV004188851	pathogenic	Cowden syndrome 1	2023-09-28	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 9256433]. 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: 17526800, 9241266, 10400993].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478652	SCV004219137	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with PTEN-hamartoma tumor syndrome diseases including Cowden syndrome (PMID: 20712882 (2010)) and Bannayan–Riley–Ruvalcaba syndrome (PMID: 29444762 (2018)). The same amino acid change (p.Ser170Arg), resulting from a different nucleotide change (c.510T>A) is classified as pathogenic. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Invitae	RCV003509648	SCV004295306	pathogenic	PTEN hamartoma tumor syndrome	2023-08-19	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 170 of the PTEN protein (p.Ser170Arg). This missense change has been observed in individual(s) with Cowden disease (PMID: 20712882). ClinVar contains an entry for this variant (Variation ID: 825458). 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. This variant disrupts the p.Ser170 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10400993, 20712882, 21194675, 21659347, 23117110). 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.