10-87933154-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000314.8(PTEN):c.395G>T(p.Gly132Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G132D) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.53

Publications

80 publications found

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 Gene-Disease associations (from GenCC):

Cowden syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
PTEN hamartoma tumor syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
macrocephaly-autism syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
leiomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
activated PI3K-delta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Bannayan-Riley-Ruvalcaba syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lhermitte-Duclos disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Proteus-like syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
glioma susceptibility 2
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

PTEN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 46 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000314.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-87933154-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92822.Status of the report is reviewed_by_expert_panel, 3 stars.

PP2

Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to leiomyosarcoma, renal cell carcinoma, Cowden syndrome 1, macrocephaly-autism syndrome, glioma susceptibility 2, PTEN hamartoma tumor syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus-like syndrome, Lhermitte-Duclos disease, activated PI3K-delta syndrome.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 10-87933154-G-T is Pathogenic according to our data. Variant chr10-87933154-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.395G>T	p.Gly132Val	missense_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2 link	c.-356G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 9		NP_001291647.1	P60484
PTEN	NM_001304717.5 link	c.914G>T	p.Gly305Val	missense_variant	Exon 6 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-356G>T		5_prime_UTR_variant	Exon 4 of 9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.395G>T	p.Gly132Val	missense_variant	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cowden syndrome 1

Pathogenic:2

Sep 27, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. 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: 16752378, 16773562, 21194675]. -

Jul 01, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:2

Oct 04, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: significantly reduced lipid phosphatase activity (Mighell et al., 2018); 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: 10923032, 10096247, 16752378, 23161105, 9256433, 26800850, 27221918, 21659347, 16773562, 27059323, 30787465, 24475377, 19457929, 29706350, 35227301, 32157856) -

Oct 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PTEN: PM1, PM2, PM5, PS4:Moderate, PP2, PP3 -

PTEN-related disorder

Pathogenic:1

Nov 20, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PTEN c.395G>T variant is predicted to result in the amino acid substitution p.Gly132Val. This variant was reported in multiple unrelated individuals with PTEN hamartoma tumor syndrome, including at least one de novo case (Tekin et al. 2006. PubMed ID: 16752378; Sarquis et al. 2006. PubMed ID: 16773562; Pilarski et al. 2011. PubMed ID: 21659347; Table S1, Pena-Couso et al. 2022. PubMed ID: 35227301). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

PTEN hamartoma tumor syndrome

Pathogenic:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 132 of the PTEN protein (p.Gly132Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pediatric PTEN hamartoma tumor syndrome, with unusual phenotypic manifestations and Cowden syndrome (PMID: 16752378, 16773562, 21659347; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7852). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) 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: 29706350). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Nov 30, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G132V pathogenic mutation (also known as c.395G>T), located in coding exon 5 of the PTEN gene, results from a G to T substitution at nucleotide position 395. The glycine at codon 132 is replaced by valine, an amino acid with dissimilar properties. This variant has been described in multiple individuals with a clinical diagnosis of Cowden syndrome (Ambry internal data; Sarquis MS et al. Am J Hum Genet, 2006 Jul;79:23-30; Tekin M et al. Am. J. Med. Genet. A 2006 Jul; 140(13):1472-5). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955). Another alteration at the same codon, p.G132D (c.395G>A), has been detected in several individuals that either met clinical criteria for PTEN hamartoma tumor syndrome (PHTS) or had features consistent with PHTS (Heindl M et al. Gastroenterology, 2012 May;142:1093-1096.e6; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Busch RM et al. Genet. Med., 2013 Jul;15:548-53; Frazier TW et al. Mol. Psychiatry, 2015 Sep;20:1132-8; Chen HH et al. J. Allergy Clin. Immunol., 2017 Feb;139:607-620.e15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Glioma susceptibility 2

Pathogenic:1

Nov 17, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

3.8

PhyloP100

9.5

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-8.4

REVEL

Pathogenic

0.99

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.98

Loss of catalytic residue at V133 (P = 0.0811);

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

5.2

Varity_R

0.99

gMVP

1.0

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over