Submissions for variant NM_000314.8(PTEN):c.373A>G (p.Lys125Glu)

dbSNP: rs1554898127

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001817633	SCV002072140	likely pathogenic	not provided	2017-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002542697	SCV002957835	uncertain significance	PTEN hamartoma tumor syndrome	2022-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 125 of the PTEN protein (p.Lys125Glu). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects PTEN function (PMID: 20926450, 21828076). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with PTEN-related conditions.
Ambry Genetics	RCV004040997	SCV003642767	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-01	criteria provided, single submitter	clinical testing	The c.373A>G (p.K125E) alteration is located in exon 5 (coding exon 5) of the PTEN gene. This alteration results from an A to G substitution at nucleotide position 373, causing the lysine (K) at amino acid position 125 to be replaced by a glutamic acid (E). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with clinical features of PTEN hamartoma tumor syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. This variant was identified in sporadic primary colorectal carcinomas and demonstrated predominant nuclear localization as well as significantly reduced ATP binding activity (Lobo, 2009). In a yeast-based lipid phosphatase activity assay, this variant demonstrated deficient function (Rodríguez-Escudero, 2011), and in another functional study, this variant demonstrated reduced p53 transcriptional activity and was not able to reduce phospho-AKT, cyclin D1 levels (He, 2011). In addition, this variant demonstrated impaired lipid phosphatase activity and showed aberrant subcellular localization with predominant nuclear localization (He, 2013). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell, 2018). This variant demonstrated wild type-like intracellular protein abundance in a multiplex functional assay (Matreyek, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Myriad Genetics, Inc.	RCV003451963	SCV004188766	likely pathogenic	Cowden syndrome 1	2023-09-27	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 19457929, 20926450]. This variant is expected to disrupt protein structure [Myriad internal data].