10-87933037-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2PS4_SupportingPM1PS2PS3_SupportingPM2

This summary comes from the ClinGen Evidence Repository: PTEN c.278A>G (p.His93Arg) 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(s) ClinVar Organization ID: 26957)PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel.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.PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 26579216, 25647146, 20718038, 21828076, 29373119, 29785012, 29706350)PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 15805158, internal laboratory contributor(s) ClinVar Organization ID: 26957) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000381/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:8

Conservation

PhyloP100: 8.87

Publications

56 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 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.

PM1

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 rank	MANE	Protein
PTEN	NM_000314.8 link	c.278A>G	p.His93Arg	missense_variant	Exon 5 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.797A>G	p.His266Arg	missense_variant	Exon 6 of 10		NP_001291646.4
PTEN	NM_001304718.2 link	c.-473A>G		5_prime_UTR_variant	Exon 4 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.278A>G	p.His93Arg	missense_variant	Exon 5 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000248

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:3

Nov 28, 2018

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.278A>G (p.His93Arg) 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(s) ClinVar Organization ID: 26957) PM1: Located at a residue within a catalytic motif as defined by the ClinGen PTEN Expert Panel. 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. PS3_P: Abnormal in vitro cellular assay or transgenic model with phenotype different from wild type that does not meet PS3. (PMID 26579216, 25647146, 20718038, 21828076, 29373119, 29785012, 29706350) PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (PMID 15805158, internal laboratory contributor(s) ClinVar Organization ID: 26957) -

Feb 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.His93Arg variant in PTEN has been reported in 2 individuals with clinical features of PTEN-associated disorders, including 1 de novo case with confirmed maternity and paternity (Butler 2005, Henderson 2014). It was absent from large population studies. Several in vitro and in vivo functional studies support an impact on protein function (Redfern 2010, Rodriguez-Escudero 2011, He 2015, Johnston 2015, Fricano-Kugler 2018, Matreyek 2018). In addition, computational prediction tools and conservation analyses are consistent with pathogenicity. Additionally, this variant was classified as pathogenic on 11/28/18 by the ClinGen-approved PTEN variant expert panel (Variation ID 7848). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PTEN Hamartoma Tumor Syndrome. ACMG/AMP Criteria applied: PS2, PM2, PP2, PP3, PS3_Supporting, PS4_Supporting. -

Nov 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 93 of the PTEN protein (p.His93Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 15805158, 24345843, 25647146). ClinVar contains an entry for this variant (Variation ID: 7848). 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: 20718038, 21828076, 22505997, 25647146, 26579216). This variant disrupts the p.His93 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9685848, 10866302, 21828076, 24778394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 09, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cowden syndrome 1

Pathogenic:1

Sep 26, 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: 32350270, 20718038, 25647146]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 22, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.H93R pathogenic mutation (also known as c.278A>G), located in coding exon 5 of the PTEN gene, results from an A to G substitution at nucleotide position 278. The histidine at codon 93 is replaced by arginine, an amino acid with highly similar properties. In one study, this alteration was detected as a de novo occurrence (paternity confirmed) in an individual with macrocephaly (+8SD), macrosomia, severe speech delay, autistic behavior, adenoidectomy, ear infections, mild bilateral epicanthal folds, and a flattened nasal bridge (Butler MG et al. J. Med. Genet., 2005 Apr;42:318-21). This alteration has also been detected in an individual with PHTS (PTEN hamartoma tumor syndrome) and EGID (eosinophilic gastrointestinal disorders) (Henderson CJ et al. J. Pediatr. Gastroenterol. Nutr., 2014 May;58:553-60). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was defined as wild-type like (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955), and this variant demonstrated possibly wild-type like intracellular protein abundance on one multiplex functional assay (Matreyek KA et al. Nat Genet, 2018 Jun;50:874-882). However, in multiple other functional studies performed on this alteration, authors have found that this alteration reduces phosphatase activity (but does not completely eliminate it), reduces PTEN enzyme activity, and impacts membrane binding (Redfern RE et al. Protein Sci., 2010 Oct;19:1948-56; Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42; Johnston SB et al. Biochemistry, 2015 Feb;54:1576-82). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Macrocephaly-autism syndrome

Pathogenic:1

Apr 01, 2005

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.61

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PhyloP100

8.9

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.88

Loss of catalytic residue at D92 (P = 0.1258);

MVP

1.0

MPC

2.5

ClinPred

1.0

GERP RS

5.1

Varity_R

0.94

gMVP

0.99

Mutation Taster

=1/99

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