Submissions for variant NM_000314.8(PTEN):c.107G>A (p.Gly36Glu)

dbSNP: rs1554893792

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV003451292	SCV004183293	pathogenic	PTEN hamartoma tumor syndrome	2023-10-11	reviewed by expert panel	curation	NM_000314.8(PTEN):c.107G>A (p.Gly36Glu) meets criteria to be classified as 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (internal laboratory contributor: SCV001781083.1) PS3_M: Functional studies supportive of a damaging effect on the gene or gene product. Score of this variant = -1.797438259 (≤ -1.11) on a high throughput phosphatase assay (PMID:29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (internal laboratory contributor: SCV001781083.1) PM2_P: Absent in gnomAD. 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 = 0.98).
Ambry Genetics	RCV000565926	SCV000676257	pathogenic	Hereditary cancer-predisposing syndrome	2019-07-25	criteria provided, single submitter	clinical testing	The p.G36E pathogenic mutation (also known as c.107G>A), located in coding exon 2 of the PTEN gene, results from a G to A substitution at nucleotide position 107. The glycine at codon 36 is replaced by glutamic acid, an amino acid with similar properties. This variant was confirmed de novo in a child with clinical features of PTEN hamartoma tumor syndrome (PHTS) (Ambry internal data). Based on an internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Lee CU et al. Angew. Chem. Int. Ed. Engl., 2015 Nov;54:13796-800). Another alteration at the same position, p.G36R, has been reported as likely pathogenic based on identification in a proband meeting clinical diagnostic criteria for PHTS and demonstrating deficient phosphatase activity in a functional study (Celebi JT et al. Exp. Dermatol., 2000 Apr;9:152-6; Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251390	SCV001426976	uncertain significance	not specified	2020-07-16	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.107G>A (p.Gly36Glu) results in a non-conservative amino acid change located in the Protein-tyrosine phosphatase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The PTEN codon 36 is reported as frequently mutated somatically, particularly in GBM, and the p.G36E variant has been reported somatically in GBM, endometrial and esopho-gastric cancers (Bilbao_2006, Werner_2013, cosmic). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001559024	SCV001781083	pathogenic	not provided	2019-07-02	criteria provided, single submitter	clinical testing	Previously reported as a somatic variant in glioblastoma, but has not been reported in the germline, to our knowledge (The Cancer Genome Atlas (TCGA) Research Network, 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect, and a functional study found this variant to result in decreased phosphatase activity (Mighell 2018); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23161105, 27481051, 29706350, 22536362)
Myriad Genetics, Inc.	RCV003451291	SCV004188755	likely pathogenic	Cowden syndrome 1	2023-09-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 32350270].