Submissions for variant NM_000314.8(PTEN):c.379G>A (p.Gly127Arg)

dbSNP: rs587781255

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479167	SCV000568255	likely pathogenic	not provided	2016-11-08	criteria provided, single submitter	clinical testing	This variant is denoted PTEN c.379G>A at the cDNA level, p.Gly127Arg (G127R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant was observed in several individual that met clinical diagnostic criteria for Cowden syndrome and in an individual with multiple primary malignant tumors (Lachlan 2007, Pal 2012, Whitworth 2015) . Additionally, in vivo tumor formation assays and gene expression profiling performed by Kim et al. (2016) inferred that this variant would exhibit significantly distinct protein expression from wild type. PTEN Gly127Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PTEN Gly127Arg occurs at a position that is conserved across species and is located in ATP binding motif and the phosphatase core domain (Lee 1999, Lobo 2009). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider PTEN Gly127Arg to be a likely pathogenic variant.
Ambry Genetics	RCV001021176	SCV001182757	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-02-07	criteria provided, single submitter	clinical testing	The p.G127R variant (also known as c.379G>A), located in coding exon 5 of the PTEN gene, results from a G to A substitution at nucleotide position 379. The glycine at codon 127 is replaced by arginine, an amino acid with dissimilar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with PTEN hamartoma tumor syndrome (PHTS) (Ambry internal data). This variant has been identified in patients reported as meeting clinical diagnostic criteria for Cowden syndrome (CS), or with multiple features of CS, or diagnosed with multiple primary tumors (Lachlan KL et al. J Med Genet. 2007 Sep;44(9):579-85; Pal A et al. N Engl J Med. 2012 Sep 13;367(11):1002-11; Whitworth J et al. Eur J Hum Genet. 2015 May;23(5):581-7). 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). This variant demonstrated low intracellular protein abundance in a massively parallel functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). (Pena-Couso L et al. Orphanet J Rare Dis, 2022 Feb;17:85). 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.
Myriad Genetics, Inc.	RCV003453057	SCV004189559	likely pathogenic	Cowden syndrome 1	2023-11-15	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: 17526800]. Functional studies indicate this variant impacts protein function [PMID: 32442409, 32366478]. This variant is expected to disrupt protein structure [Myriad internal data].
Medical Molecular Genetics, University of Birmingham	RCV000128454	SCV000172155	pathogenic	PTEN hamartoma tumor syndrome	2012-08-01	no assertion criteria provided	clinical testing	Clinically treated as causative