rs398123316

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP2PP3PM2_SupportingPS3_ModeratePS4_Supporting

This summary comes from the ClinGen Evidence Repository: PTEN c.182A>G (p.His61Arg) meets criteria to be classified as likely 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_M: Massively parallel functional assay interrogating phosphatase activity demonstrating a statistically significant difference from wild type (PMID:29706350).PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID:28526761). PM2_P: 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. PP3: REVEL score = 0.981. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000332/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Consequence

PTEN
NM_000314.8 missense

Scores

15

3

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:5U:1

Conservation

PhyloP100: 8.65

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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.

PP2

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

PP3

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 link	c.182A>G	p.His61Arg	missense_variant	3/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.701A>G	p.His234Arg	missense_variant	4/10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-541-5516A>G		intron_variant			NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.182A>G	p.His61Arg	missense_variant	3/9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

Cov.:

30

GnomAD4 genome

Cov.:

32

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:2Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Dec 01, 2023	PTEN c.182A>G (p.His61Arg) meets criteria to be classified as likely 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_M: Massively parallel functional assay interrogating phosphatase activity demonstrating a statistically significant difference from wild type (PMID: 29706350). PS4_P: Proband(s) with phenotype specificity score of 1-1.5 (PMID: 28526761). PM2_P: 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. PP3: REVEL score = 0.981. -
Pathogenic, criteria provided, single submitter	clinical testing	Herman Laboratory, Nationwide Children's Hospital	Mar 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 20, 2022	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. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTEN protein function. ClinVar contains an entry for this variant (Variation ID: 189402). This missense change has been observed in individuals with clinical features of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome (PMID: 20600018, 21194675, 21659347, 28526761). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 61 of the PTEN protein (p.His61Arg). -

Cowden syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Sep 26, 2023

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 24778394, 21659347, 21194675]. Functional studies indicate this variant impacts protein function [PMID: 10866302]. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2024

The p.H61R variant (also known as c.182A>G) is located in coding exon 3 of the PTEN gene. This alteration results from an A to G substitution at nucleotide position 182. The histidine at codon 61 is replaced by arginine, an amino acid with similar properties. This alteration has been reported in individuals meeting relaxed International Cowden Consortium operational criteria for Cowden syndrome (Tan MH et al. Am J Hum Genet. 2011 Jan 7;88(1):42-56), as well as an individual with Bannayan-Riley-Ruvalcaba syndrome (Hansen-Kiss E et al. J. Med. Genet. 2017 07;54:471-478). 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). This variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). 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. 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

D

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

28

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.99

D

M_CAP

Pathogenic

0.82

D

MetaRNN

Pathogenic

0.95

D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

4.1

H

PrimateAI

Pathogenic

0.93

D

PROVEAN

Pathogenic

-7.3

D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0020

D

Sift4G

Uncertain

0.0050

D

Polyphen

1.0

D

Vest4

0.92

MutPred

0.73

Gain of MoRF binding (P = 0.029);

MVP

1.0

MPC

2.6

ClinPred

1.0

D

GERP RS

5.5

Varity_R

0.90

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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: rs398123316; hg19: chr10-89685287; COSMIC: COSV64290165;