Submissions for variant NM_000314.8(PTEN):c.518G>A (p.Arg173His)

gnomAD frequency: 0.00001  dbSNP: rs121913294

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484180	SCV000566605	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han et al., 2000; Rodriguez-Escudero et al., 2011; Mighell et al., 2018); 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: 21828076, 25527629, 23335809, 30720243, 29625052, 24721394, 20533527, 23161105, 28526761, 17526800, 21659347, 26800850, 28201779, 28304377, 28984400, 16506206, 11875759, 20718038, 18986487, 29706350, 19265751, 24475377, 33482836, 36192478, 10866302)
Herman Laboratory, Nationwide Children's Hospital	RCV000490595	SCV000579279	pathogenic	PTEN hamartoma tumor syndrome	2017-03-01	criteria provided, single submitter	clinical testing
Invitae	RCV000490595	SCV000645595	pathogenic	PTEN hamartoma tumor syndrome	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 173 of the PTEN protein (p.Arg173His). This variant is present in population databases (rs121913294, gnomAD 0.01%). This missense change has been observed in individuals with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 20533527, 23335809; Invitae). ClinVar contains an entry for this variant (Variation ID: 376032). 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: 10866302). This variant disrupts the p.Arg173 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10866302, 17526800, 25669429, 28475857). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000490595	SCV000711962	likely pathogenic	PTEN hamartoma tumor syndrome	2016-10-20	criteria provided, single submitter	clinical testing	The p.Arg173His variant has been reported in 4 individuals with clinical feature s of Cowden syndrome (Lachlan 2007, Mcbride 2010, Bubien 2013) and segregated wi th disease in 2 affected relatives from 2 different families (Lachlan 2007, Varg a 2004). In addition, it segregated with macrocephaly in 1 relative from a third family (McBride 2010). This variant has been identified in 1/10324 African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs121913294). This variant has been observed as a somatic mutation in t umors, including glioblastoma (Duerr 1998) and colorectal cancer (Day 2013). The p.Arg173His variant is associated with decreased protein activity in vitro (Han 2000, Rodriguez-Escudero 2011). However, these types of assays may not accurate ly represent biological function. In summary, although additional studies are re quired to fully establish its clinical significance, the p.Arg173His variant is likely pathogenic in an autosomal dominant manner.
CeGaT Center for Human Genetics Tuebingen	RCV000484180	SCV001334626	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002289517	SCV002581229	pathogenic	Cowden syndrome 1	2021-12-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002338980	SCV002643221	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	The p.R173H variant (also known as c.518G>A), located in coding exon 6 of the PTEN gene, results from a G to A substitution at nucleotide position 518. The arginine at codon 173 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with clinical features of PTEN-hamartoma tumor syndrome (Hansen-Kiss E et al. J. Med. Genet., 2017 07;54:471-478; Lachlan KL et al. J. Med. Genet., 2007 Sep;44:579-85; Varga EA et al. Genet. Med., 2009 Feb;11:111-7; McBride KL et al. Autism Res, 2010 Jun;3:137-41; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; van der Velden JJ. et al. Int. J. Dermatol. 2008 Nov;47 Suppl 1:45-8). In one study, functional assays demonstrated that this alteration inactivates phosphastase activity (Han SY et al. Cancer Res., 2000 Jun;60:3147-51); however, in vivo yeast assays demonstrated partial phosphastase activity in another study (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). Another study determined that p.R173H has an intermediate effect on regulating p53 and Gata3 levels compared to wild-type and nonsense alleles (Xu J et al. Transl Oncol, 2014 Apr;7:196-205.e1). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002289517	SCV002820282	pathogenic	Cowden syndrome 1		criteria provided, single submitter	clinical testing	The missense variant p.R173H in PTEN (NM_000314.8) has been reported before both in a patient with developmental delay (Varga EA et al) as well as in patients with PTEN related hamartoma syndrome (Bubien et al; Hansen et al).Functional studies revealed reduced phosphatse activity (Rodriguez-Escudero et al). The variant has been submitted to ClinVar as Pathogenic/Likely Pathogenic. The p.R173H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 173 of PTEN is conserved in all mammalian species. The nucleotide c.518 in PTEN is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV000490595	SCV004046133	pathogenic	PTEN hamartoma tumor syndrome		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in patients with PTEN hamartoma tumor syndrome (PMID: 17526800, 19265751, 23335809, 20533527, 28526761). In vitro assays showed that this variant is associated with decreased phosphatase activity (PMID: 21828076, 10866302). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.001 % (2/251148) and thus is presumed to be rare. The c.518G>A (p.Arg173His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.518G>A (p.Arg173His) variant is classified as Pathogenic.
Myriad Genetics, Inc.	RCV002289517	SCV004188723	likely pathogenic	Cowden syndrome 1	2023-09-28	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17526800, 18626099, 19265751, 20533527, 23335809].
Database of Curated Mutations (DoCM)	RCV000432256	SCV000504815	likely pathogenic	Neoplasm of brain	2015-07-14	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000484180	SCV000692014	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000484180	SCV001954946	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000484180	SCV001973342	likely pathogenic	not provided		no assertion criteria provided	clinical testing