Submissions for variant NM_000314.8(PTEN):c.755A>G (p.Asp252Gly)

dbSNP: rs121909239

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000758222	SCV000886855	pathogenic	PTEN hamartoma tumor syndrome	2023-06-14	reviewed by expert panel	curation	NM_000314.8(PTEN):c.755A>G (p.Asp252Gly) variant 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). PS6_S: One proband with presumed de novo occurrence (maternity/paternity not confirmed) for a patient with highly specific phenotype. (PMID: 23335809). PS3_M: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. 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=0.971) PM2_P: Absent in large sequenced populations OR present at extremely low (<0.00001, 0.001%) allele frequency in the gnomAD cohort. (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID: 23335809).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758222	SCV000946953	pathogenic	PTEN hamartoma tumor syndrome	2024-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 252 of the PTEN protein (p.Asp252Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features consistent with PTEN hamartoma tumor syndrome (PMID: 15805158, 21659347, 21828076). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7849). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 25527629, 26579216, 29785012). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001775539	SCV002013433	pathogenic	not provided	2023-05-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced nuclear localization, protein expression, and lipid phosphastase activity, and inability to rescue neuronal hypertrophy in a mouse model (Rodriguez-Escudero et al., 2011; Fricano-Kugler et al., 2018; Spinelli et al., 2015; Mighell et al., 2018; Wong et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29706633, 29706350, 27535533, 26800850, 31086789, 23161105, 27221918, 26053092, 26579216, 17286265, 29373119, 17427195, 27405757, 21659347, 32150788, 23335809, 18626510, 29785012, 25527629, 15805158, 21828076)
Ambry Genetics	RCV002390096	SCV002670872	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-06	criteria provided, single submitter	clinical testing	The p.D252G pathogenic mutation (also known as c.755A>G), located in coding exon 7 of the PTEN gene, results from an A to G substitution at nucleotide position 755. The aspartic acid at codon 252 is replaced by glycine, an amino acid with similar properties. This mutation was identified in a child with developmental delay and extreme macrocephaly (Butler MG et al. J Med Genet, 2005 Apr;42:318-21) and was found to be de novo in an individual with oral papillomas, facial papules, and extreme macrocephaly (personal communication, Bubien V et al. J Med Genet, 2013 Apr;50:255-63). In one study, D252G demonstrated greater than a 50% reduction in lipid phosphatase activity compared to wild type PTEN (Wong CW et al. FEBS J, 2020 11;287:4848-4861). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 06;50:874-882). Other assays also support reduced protein expression and/or functional activity compared to wild type (He X et al. Mol Autism, 2015 Nov;6:63; Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955; Mingo J et al. Eur J Hum Genet, 2018 08;26:1180-1187; Post KL et al. Nat Commun, 2020 04;11:2073). Based on structural analysis, this p.D252G is deleterious (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 amino acid position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003450620	SCV004188735	likely pathogenic	Cowden syndrome 1	2023-09-29	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 25527629, 26579216, 27405757]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15805158, 21194675, 23335809].
Baylor Genetics	RCV003460437	SCV004204851	likely pathogenic	Glioma susceptibility 2	2022-08-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000758222	SCV004847792	likely pathogenic	PTEN hamartoma tumor syndrome	2020-01-23	criteria provided, single submitter	clinical testing	The p.Asp252Gly variant in PTEN has been reported in at least 3 individuals with features of PTEN hamartoma tumor syndrome (Bubien 2013, Pilarski 2011, Butler 2005). This variant was absent from large population studies. It was classified as Likely pathogenic on July 25, 2018 by the ClinGen-approved PTEN Variant Curation expert panel (Variation ID 7849); note, this expert panel also indicated via personal communication that one of the individuals was reportedly a de novo occurrence, though paternityand maternity were not confirmed. In vitro functional studies support an impact on protein function (Spinelli 2015, Rodriguez-Escudero 2011, Fricano-Kugler 2018). PTEN is defined by the PTEN expert Panel as a gene that has low rate of benign missense variation and where missense variants are a common mechanism of disease. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant PTEN hamartoma tumor syndrome. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP2, PS3_Supporting
OMIM	RCV000008299	SCV000028506	pathogenic	Macrocephaly-autism syndrome	2005-04-01	no assertion criteria provided	literature only