10-87933223-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP2PS4PS3PM6PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.464A>G (p.Tyr155Cys) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS3: Phosphatase activity <50% of wild type (PMID 21828076, 10866302, 29706350)PS4: Probands with phenotype specificity score of 4-15.5 (PMID 23399955, internal laboratory contributors SCV000579967.3, ClinVar Organization ID: 19864)PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957)PM2: Absent in large sequenced populations (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/CA16613246/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTEN
NM_001304718.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:16U:1

Conservation

PhyloP100: 8.88

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PS3

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

PS4

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

PM2

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

PM6

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 rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.464A>G	p.Tyr155Cys	missense_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304718.2 link	c.-287A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 4 of 9		NP_001291647.1	P60484
PTEN	NM_001304717.5 link	c.983A>G	p.Tyr328Cys	missense_variant	Exon 6 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-287A>G		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.464A>G	p.Tyr155Cys	missense_variant	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460882

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with conditions associated with PTEN-hamartoma tumor syndrome (PMID: 23399955 (2013), 21194675 (2011), 27531073 (2016), 29706646 (2018), 32664367 (2020), 33083010 (2020), 33088792 (2020), 12614768 (2003), 23335809 (2013)). Published functional studies showed that this variant causes reduced phosphatase activity compared to the wild type protein (PMID: 10866302 (2000), 21828076 (2011)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTEN hamartoma tumor syndrome

Pathogenic:3

Nov 22, 2019

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

PTEN c.464A>G (p.Tyr155Cys) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (PMID 30311380). Please see a summary of the rules and criteria codes in the "PTEN ACMG Specifications Summary" document (assertion method column). PS3: Phosphatase activity <50% of wild type (PMID 21828076, 10866302, 29706350) PS4: Probands with phenotype specificity score of 4-15.5 (PMID 23399955, internal laboratory contributors SCV000579967.3, ClinVar Organization ID: 19864) PM6_S: Two probands with presumed de novo occurrence (maternity/paternity not confirmed) in a patient with the disease and no family history. (internal laboratory contributor ClinVar Organization ID: 26957) PM2: Absent in large sequenced populations (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. -

University Health Network, Princess Margaret Cancer Centre

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant c.464 A>G is not present in population databases. It has been reported in individuals affected with PHTS (Bubien 2013, Gicquel 2003, Ngeow 2013, Andres-Pons 2007). -

Jul 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 155 of the PTEN protein (p.Tyr155Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome or PTEN hamartoma tumor syndrome (PMID: 12614768, 17942903, 23335809, 23399955, 27531073). ClinVar contains an entry for this variant (Variation ID: 404168). 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: 10866302, 17942903, 21828076). This variant disrupts the p.Tyr155 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 30181857), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Cowden syndrome 1

Pathogenic:2Uncertain:1

Sep 01, 2017

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

this variant was indentified in an individual with malformations of cortical development -

Jun 02, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10866302, 11051241, 27829222]. 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: 12614768]. -

PTEN hamartoma tumor syndromes

Pathogenic:1

Jan 14, 2019

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.464A>G (p.Tyr155Cys) variant in the PTEN gene has been reported in multiple individuals with Cowden's disease or PTEN hamartoma tumor syndrome (PMID 12614768, 17942903, 19265751, 23335809, 23399955, 27531073). This variant is absent from large databases of genetic variation in the general population. In vitro phosphatase activity assay demonstrated that the activity of the mutant protein is equivalent to a null allele (PMID 10866302). Multiple lines of algorithms predict deleterious effect of the p.Tyr155Cys change. Therefore, the c c.464A>G (p.Tyr155Cys) variant in the PTEN gene is classified as likely pathogenic. -

Papillary tumor of the pineal region

Pathogenic:1

Feb 01, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1

Pathogenic:1

May 25, 2023

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 27, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y155C pathogenic mutation (also known as c.464A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 464. The tyrosine at codon 155 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in numerous individuals with personal and/or family history consistent with PTEN Hamartoma Tumor Syndrome (Ambry internal data; Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Gicquel JJ et al. Am. J. Ophthalmol. 2003 Mar; 135(3):400-2; Bubien V et al. J. Med. Genet., 2013 Apr;50:255-63; Ngeow J et al. Gastroenterology, 2013 Jun;144:1402-9, 1409.e1-5; Nizialek E et al. Eur. J. Hum. Genet. 2015 Nov;23(11):1538-43; Driessen GJ et al. J. Allergy Clin. Immunol., 2016 12;138:1744-1747.e5; Wiszniewski W et al. Eur J Hum Genet, 2018 08;26:1121-1131; Szabo Yamashita T et al. Eur Thyroid J, 2020 Sep;9:243-246; Plamper M et al. Cells, 2020 07;9; Kim RH et al. NPJ Genom Med, 2020 Sep;5:40). In a yeast functional assay, this variant demonstrated loss of in vivo phosphatase activity (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). 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). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Glioma susceptibility 2

Pathogenic:1

Sep 12, 2023

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

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.68

MutationAssessor

Pathogenic

2.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-8.7

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.86

Loss of phosphorylation at Y155 (P = 0.0194);

MVP

0.98

MPC

2.6

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.98

gMVP

0.99

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