Submissions for variant NM_000314.8(PTEN):c.106G>A (p.Gly36Arg)

dbSNP: rs786204854

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV001885301	SCV004183291	likely pathogenic	PTEN hamartoma tumor syndrome	2023-10-11	reviewed by expert panel	curation	NM_000314.8(PTEN):c.106G>A (p.Gly36Arg) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -2.69 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_M: Probands with phenotype specificity score of 2-3.5 (PMID: 32442409, internal laboratory contributor: SCV002061526.2). PM2_P: Absent in gnomAD. PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (internal laboratory contributor: SCV002061526.2). 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. PP3: REVEL score > 0.7 (score of this variant = 0.995).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001814732	SCV002061526	pathogenic	Macrocephaly-autism syndrome; Cowden syndrome 1	2021-08-17	criteria provided, single submitter	clinical testing	PS3, PP2, PP3, PM1, PM2, PS4_Supporting
Labcorp Genetics (formerly Invitae), Labcorp	RCV001885301	SCV002165540	likely pathogenic	PTEN hamartoma tumor syndrome	2024-05-20	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 36 of the PTEN protein (p.Gly36Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Cowden syndrome (PMID: 10772390, 32442409; Invitae). ClinVar contains an entry for this variant (Variation ID: 1334551). 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: 17942903, 21828076, 25875300). 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.
Ambry Genetics	RCV002406896	SCV002722771	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-10	criteria provided, single submitter	clinical testing	The p.G36R variant (also known as c.106G>A), located in coding exon 2 of the PTEN gene, results from a G to A substitution at nucleotide position 106. The glycine at codon 36 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in one individual with clinical features of Cowden syndrome, including: trichilemmomas, oral papillomatosis, acral keratosis, breast cancer, hypothyroidism, gastrointestinal polyps, macrocephaly, and uterine fibroids (Celebi JT et al. Exp. Dermatol., 2000 Apr;9:152-6). In addition, this alteration was detected in 1 of 802 subjects undergoing PTEN genetic testing; however, individual phenotype information was not provided (Pilarski R et al. J. Med. Genet., 2011 Aug;48:505-12). 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). In a functional study using a yeast-based assay, this variant demonstrated severely reduced phosphatase activity when compared to wild type PTEN and was similar to the catalytic dead control (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov;20:4132-42). This amino acid position is highly conserved in available vertebrate species. 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV003316850	SCV004019425	likely pathogenic	Cowden syndrome 1	2023-02-09	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: 10772390, 32442409, 17942903]. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 32350270].