Submissions for variant NM_000314.8(PTEN):c.701G>A (p.Arg234Gln)

dbSNP: rs121909235

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clingen PTEN Variant Curation Expert Panel, Clingen	RCV000540379	SCV000930139	uncertain significance	PTEN hamartoma tumor syndrome	2023-06-14	reviewed by expert panel	curation	NM_000314.8(PTEN):c.701G>A (p.Arg234Gln) is currently classified as a variant of uncertain significance 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). PM2_Supporting: Absent in large sequenced populations in the gnomAD cohort. (PMID 27535533). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000540379	SCV000645613	uncertain significance	PTEN hamartoma tumor syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 234 of the PTEN protein (p.Arg234Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with glioma and/or pancreatic cancer (PMID: 12085208, 28755079). ClinVar contains an entry for this variant (Variation ID: 7840). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 12085208). 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.
Ambry Genetics	RCV000566397	SCV000665310	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-10	criteria provided, single submitter	clinical testing	The p.R234Q variant (also known as c.701G>A), located in coding exon 7 of the PTEN gene, results from a G to A substitution at nucleotide position 701. The arginine at codon 234 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in an individual with an anaplastic oligodendroglioma and benign meningioma; however, this individual did not show any clinical signs of PTEN hamartoma tumor syndrome (Staal FJ et al. Br. J. Cancer 2002 May;86:1586-91). Transfection assays by Staal et al. show the altered protein results in increased protein kinase B activity, increased cell proliferation, and diminished apoptosis, leading authors to conclude that p.R234Q has oncogenic properties. This variant is located in the C-2 domain of the PTEN protein and may affect membrane interaction (Staal FJ et al. Br. J. Cancer 2002 May;86:1586-91; Lumb CN and Sansom MSP Biophys. J. 2013 Feb;104:613-21). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566397	SCV000913519	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 234 of the PTEN protein. Experimental studies transfecting this variant into a glioma cell line lacking functional PTEN have shown that this variant results in high constitutive PKB/Akt activity, increased cell proliferation, and a failure to induce apoptosis (PMID: 12085208). This variant has been reported in individuals affected with pancreatic cancer and glioma in the literature (PMID: 12085208, 28755079), but also in control individuals (PMID: 30287823; DOI: 10.21203/rs.3.rs-792966/v1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001526987	SCV001737785	uncertain significance	not specified	2021-06-12	criteria provided, single submitter	clinical testing	Variant summary: PTEN c.701G>A (p.Arg234Gln) results in a conservative amino acid change located in the Tensin phosphatase, C2 domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251444 control chromosomes. c.701G>A has been reported in the literature as a germline variant in individuals not presenting with a classic Cowden syndrome phenotype, such as, an individual affected with anaplastic oligodendroglioma who did not have features of Cowden syndrome and no LOH of PTEN in the tumor material (Staal_2002), an 82 year old woman with pancreatic cancer whose tumor immunohistochemistry revealed a loss of PTEN protein expression an overexpression of TP53, and a K-ras p.Gly12Val mutation (Uemura_2018), and in Japanese unaffected male controls (Momozawa_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Cowden Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in increased proliferation, does not induce apoptosis and increased PKB/Akt phosphorylation (Staal_2002). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance with some submitters citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as a VUS-possibly pathogenic that could be associated with a predisposition to other cancer types.
GeneDx	RCV001555861	SCV001777346	uncertain significance	not provided	2019-09-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32710294, 25343854, 23161105, 28755079, 27221918, 26800850, 26579216, 16702501, 23442912, 24470394, 12085208, 30287823, 27535533)
All of Us Research Program, National Institutes of Health	RCV000540379	SCV004838573	uncertain significance	PTEN hamartoma tumor syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 234 of the PTEN protein. Experimental studies transfecting this variant into a glioma cell line lacking functional PTEN have shown that this variant results in high constitutive PKB/Akt activity, increased cell proliferation, and a failure to induce apoptosis (PMID: 12085208). This variant has been reported in individuals affected with pancreatic cancer and glioma in the literature (PMID: 12085208, 28755079), but also in control individuals (PMID: 30287823; DOI: 10.21203/rs.3.rs-792966/v1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000008288	SCV005052551	uncertain significance	Glioma susceptibility 2	2024-03-19	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004576888	SCV005060882	uncertain significance	Macrocephaly-autism syndrome		criteria provided, single submitter	clinical testing	The missense c.1220G>A(p.Arg407Gln) variant in PTEN gene has been reported in heterozygous state in an individual affected with PTEN related disorder (Staal, F., et al., 2002). Experimental studies have shown that altered protein results in increased protein kinase B activity, increased cell proliferation, and diminished apoptosis (Staal, F., et al., 2002). This variant is absent in gnomAD Exomes. This variant has been submitted to clinvar database as Pathogenic/ Uncertain significance (multiple submissions). For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
OMIM	RCV000008288	SCV000028495	risk factor	Glioma susceptibility 2	2002-05-20	no assertion criteria provided	literature only
OMIM	RCV000008289	SCV000028496	pathogenic	Meningioma	2002-05-20	no assertion criteria provided	literature only