Submissions for variant NM_000314.8(PTEN):c.45A>T (p.Arg15Ser)

dbSNP: rs1064794096

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480969	SCV000567809	pathogenic	not provided	2018-06-11	criteria provided, single submitter	clinical testing	This variant is denoted PTEN c.45A>T at the cDNA level, p.Arg15Ser (R15S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGT). This variant has been reported in at least three individuals with features of PTEN Hamartoma Tumor syndrome, including an individual meeting Cowden syndrome diagnostic criteria, another described as Cowden-like", and as a de novo variant in a child with macrocephaly and developmental delay (Sarquis 2006, Nagy 2011, Vanderver 2014). Functional assays have revealed loss of lipid phosphatase and growth suppression activities and aberrant protein cellular localization (Furnari 1998, Denning 2007, Andres-Pons 2007, Gil 2015). PTEN Arg15Ser was not observed in large population cohorts (Lek 2016). This variant is located in the Phosphatase domain and N-terminal nuclear localization signal (Molinari 2014, Gil 2015). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available information, we consider PTEN Arg15Ser to be pathogenic."
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047309	SCV001211259	likely pathogenic	PTEN hamartoma tumor syndrome	2022-11-15	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 15 of the PTEN protein (p.Arg15Ser). This missense change has been observed in individuals with Cowden syndrome (CS) or clinical features of CS (PMID: 16773562, 21417916, 21659347, 24375884, 32037394). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 17942903, 25875300, 29706350). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function. ClinVar contains an entry for this variant (Variation ID: 419769).
Ambry Genetics	RCV003298549	SCV004001638	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-24	criteria provided, single submitter	clinical testing	The p.R15S pathogenic mutation (also known as c.45A>T), located in coding exon 1 of the PTEN gene, results from an A to T substitution at nucleotide position 45. The arginine at codon 15 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in several individuals with PTEN-related features (Pilarski R et al. J Med Genet. 2011 Aug;48:505-12; Nagy R et al. Thyroid. 2011 May;21:505-10; Sarquis MS et al. Am J Hum Genet. 2006 Jul;79:23-30). This alteration was confirmed de novo in an 18-month-old with significant macrocephaly, motor skill developmental delays, and posterior periventricular multifocal white matter abnormalities (Vanderver A et al. Am J Med Genet A. 2014 Mar;164A:627-33). A different alteration leading to the same amino acid substitution, c.45A>C (p.R15S), has been described in individuals with PTEN-related features (Reuter MS et al. Genet Med, 2020 Jun;22:1015-1024; Ambry internal data). In a 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). Additional functional studies have demonstrated wildtype-like protein stability but significantly reduced phosphatase activity (Andrés-Pons A et al. Cancer Res. 2007 Oct;67:9731-9; Gil A et al. PLoS One 2015 Apr;10(4):e0119287; Mingo J et al. Eur J Hum Genet. 2018 08;26:1180-1187). 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). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis and is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.