Submissions for variant NM_000314.8(PTEN):c.493G>A (p.Gly165Arg)

dbSNP: rs587782603

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000690443	SCV001244250	pathogenic	PTEN hamartoma tumor syndrome	2019-11-22	reviewed by expert panel	curation	PTEN c.493G>A (p.Gly165Arg) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor SCV000617324.2) PS3: Phosphatase activity <50% of wild type (PMID 29706350, 9256433, 10866302) PM2: Absent in large sequenced populations (PMID 27535533). PP2: PTEN is defined by the PTEN Expert Panel as a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809, internal laboratory contributor SCV000617324.2)
Ambry Genetics	RCV000491530	SCV000580051	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	The p.G165R variant (also known as c.493G>A) is located in coding exon 6 of the PTEN gene. The glycine at codon 165 is replaced by arginine, an amino acid with dissimilar properties. This variant is located in the PTP catalytic domain. In two functional studies, in vitro phosphatase activity was severely reduced compared to the wild type PTEN protein and was similar to a catalytic dead control (Myers MP et al. Proc. Natl. Acad. Sci. U.S.A., 1997 Aug;94:9052-7; Han SY et al. Cancer Res., 2000 Jun;60:3147-51). 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 05;102:943-955). Two other alterations at this position, p.G165E and p.G165V, have been observed to result in reduced in vivo activity in yeast (Rodr&iacute;guez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). In one study of gene expression profiles in breast cancers, the p.G165R variant was detected in the germline of an individual with breast cancer at 59 years and meeting a medical genetics diagnosis of suspected Cowden syndrome (Banneau G et al. Breast Cancer Res. 2010;12(4):R63). This alteration has also been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Pilarski R et al. J. Med. Genet., 2011 Aug;48:505-12). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000522601	SCV000617324	pathogenic	not provided	2017-08-16	criteria provided, single submitter	clinical testing	The G165R variant in the PTEN gene was observed in at least one individual with breast cancer, and in one individual undergoing clinical testing of the PTEN gene (Banneau et al., 2010; Pilarksi et al., 2011). Functional studies show that G165R significantly decreases PTEN phosphatase activity (Myers et al., 1997; Han et al., 2000). This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al., 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. This substitution occurs at a position that is conserved across species and is located in the phosphatase domain (Molinari et al., 2014). Based on currently available evidence, we consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690443	SCV000818127	pathogenic	PTEN hamartoma tumor syndrome	2024-03-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 165 of the PTEN protein (p.Gly165Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 20712882, 21194675, 21659347; Invitae). ClinVar contains an entry for this variant (Variation ID: 428256). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PTEN function (PMID: 9256433, 10866302). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV003139692	SCV003806528	likely pathogenic	Cowden syndrome 1	2023-01-31	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20712882, 32442409, 21194675, 35227301]. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant is expected to disrupt protein structure [internal Myriad data].
Baylor Genetics	RCV004568616	SCV005052567	pathogenic	Glioma susceptibility 2	2023-12-14	criteria provided, single submitter	clinical testing
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332184	SCV004040576	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research