rs587782603

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP2PS4_SupportingPS2PS3PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.493G>A (p.Gly165Arg) 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).PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor SCV000617324.2)PS3: Phosphatase activity <50% of wild type (PMID 29706350, 9256433, 10866302)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.PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809, internal laboratory contributor SCV000617324.2) LINK:https://erepo.genome.network/evrepo/ui/classification/CA377484223/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 missense, splice_region

Scores

16

2

1

Splicing: ADA: 0.9162

2

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 9.46

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 12 ACMG points.

PS2

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

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.

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.493G>A	p.Gly165Arg	missense_variant, splice_region_variant	6/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1012G>A	p.Gly338Arg	missense_variant, splice_region_variant	7/10		NP_001291646.4
PTEN	NM_001304718.2 linkuse as main transcript	c.-98-1G>A		splice_region_variant, 5_prime_UTR_variant	6/9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.493G>A	p.Gly165Arg	missense_variant, splice_region_variant	6/9	1	NM_000314.8	ENSP00000361021	P1	P60484-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

0

AN:

1460972

Hom.:

0

Cov.:

31

AF XY:

0.00

AC XY:

0

AN XY:

726828

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Nov 22, 2019	PTEN c.493G>A (p.Gly165Arg) 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). PS2: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. (Internal laboratory contributor SCV000617324.2) PS3: Phosphatase activity <50% of wild type (PMID 29706350, 9256433, 10866302) 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. PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 23335809, internal laboratory contributor SCV000617324.2) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 165 of the PTEN protein (p.Gly165Arg). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects PTEN function (PMID: 9256433, 10866302). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 428256). This missense change has been observed in individuals with Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome (PMID: 20712882, 21194675, 21659347; Invitae). This variant is not present in population databases (gnomAD no frequency). -

Cowden syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 31, 2023

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 20712882, 32442409, 21194675, 35227301]. Functional studies indicate this variant impacts protein function [PMID: 10866302]. This variant is expected to disrupt protein structure [internal Myriad data]. -

Malignant tumor of urinary bladder

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Laboratory of Urology, Hospital Clinic de Barcelona

-

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2017

The G165R variant in the PTEN gene was observed in at least one individual with breast cancer, and in one individual undergoing clinical testing of the PTEN gene (Banneau et al., 2010; Pilarksi et al., 2011). Functional studies show that G165R significantly decreases PTEN phosphatase activity (Myers et al., 1997; Han et al., 2000). This variant was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek et al., 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. This substitution occurs at a position that is conserved across species and is located in the phosphatase domain (Molinari et al., 2014). Based on currently available evidence, we consider this variant to be pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The p.G165R variant (also known as c.493G>A) is located in coding exon 6 of the PTEN gene. The glycine at codon 165 is replaced by arginine, an amino acid with dissimilar properties. This variant is located in the PTP catalytic domain. In two functional studies, in vitro phosphatase activity was severely reduced compared to the wild type PTEN protein and was similar to a catalytic dead control (Myers MP et al. Proc. Natl. Acad. Sci. U.S.A., 1997 Aug;94:9052-7; Han SY et al. Cancer Res., 2000 Jun;60:3147-51). 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 05;102:943-955). Two other alterations at this position, p.G165E and p.G165V, have been observed to result in reduced in vivo activity in yeast (Rodríguez-Escudero I et al. Hum. Mol. Genet. 2011 Nov; 20(21):4132-42). In one study of gene expression profiles in breast cancers, the p.G165R variant was detected in the germline of an individual with breast cancer at 59 years and meeting a medical genetics diagnosis of suspected Cowden syndrome (Banneau G et al. Breast Cancer Res. 2010;12(4):R63). This alteration has also been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am. J. Hum. Genet. 2011 Jan; 88(1):42-56; Pilarski R et al. J. Med. Genet., 2011 Aug;48:505-12). This variant was not reported in population-based 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. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Glioma susceptibility 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

D

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

35

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.97

D

M_CAP

Pathogenic

0.88

D

MetaRNN

Pathogenic

0.98

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.5

H

MutationTaster

Benign

1.0

D

PrimateAI

Pathogenic

0.94

D

PROVEAN

Pathogenic

-7.3

D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D

Sift4G

Uncertain

0.0030

D

Polyphen

1.0

D

Vest4

0.99

MutPred

0.82

Gain of MoRF binding (P = 0.0123);

MVP

0.98

MPC

2.6

ClinPred

1.0

D

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.94

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Benign

0.62

SpliceAI score (max)

0.060

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.

Other links and lift over

dbSNP: rs587782603; hg19: chr10-89711875; COSMIC: COSV64289126; COSMIC: COSV64289126;