rs121909235

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP2PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000551/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:9O:1

Conservation

PhyloP100: 9.53

Variant links:

Genes affected

PTEN (HGNC:9588): (phosphatase and tensin homolog) This gene was identified as a tumor suppressor that is mutated in a large number of cancers at high frequency. The protein encoded by this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases. Unlike most of the protein tyrosine phosphatases, this protein preferentially dephosphorylates phosphoinositide substrates. It negatively regulates intracellular levels of phosphatidylinositol-3,4,5-trisphosphate in cells and functions as a tumor suppressor by negatively regulating AKT/PKB signaling pathway. The use of a non-canonical (CUG) upstream initiation site produces a longer isoform that initiates translation with a leucine, and is thought to be preferentially associated with the mitochondrial inner membrane. This longer isoform may help regulate energy metabolism in the mitochondria. A pseudogene of this gene is found on chromosome 9. Alternative splicing and the use of multiple translation start codons results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Feb 2015]

PTEN links:

PTEN (HGNC:):

PTEN links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8 linkuse as main transcript	c.701G>A	p.Arg234Gln	missense_variant	7/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1220G>A	p.Arg407Gln	missense_variant	8/10		NP_001291646.4	P60484
PTEN	NM_001304718.2 linkuse as main transcript	c.110G>A	p.Arg37Gln	missense_variant	7/9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.701G>A	p.Arg234Gln	missense_variant	7/9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	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. -
Uncertain significance, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Jun 14, 2023	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. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 19, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 10, 2021	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. -

Glioma susceptibility 2

Uncertain:1Other:1

risk factor, no assertion criteria provided	literature only	OMIM	May 20, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 19, 2024	- -

Meningioma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 20, 2002

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 12, 2021

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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2019

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) -

Macrocephaly-autism syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

D;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.7

N;.

REVEL

Pathogenic

0.70

Sift

Benign

0.094

T;.

Sift4G

Benign

0.14

T;T

Polyphen

0.98

D;.

Vest4

0.95

MutPred

0.44

Loss of sheet (P = 0.0181);.;

MVP

0.97

MPC

1.3

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over