10-87952142-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP2PP1PS4_ModeratePS3PM2PS2

This summary comes from the ClinGen Evidence Repository: PTEN c.517C>T (p.R173C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column).PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 17526800, PMID 22628360, internal laboratory contributor(s) SCV000222220.10)PS3: Phosphatase activity <50% of wild type. (PMID 10866302)PM2: Absent in large sequenced populations (PMID 27535533).PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 22628360, PMID 17526800, PMID 17526801)PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 22628360)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/CA000498/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 7.46

Publications

134 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 14 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.

PP1

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.517C>T	p.Arg173Cys	missense_variant	Exon 6 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.1036C>T	p.Arg346Cys	missense_variant	Exon 7 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-75C>T		5_prime_UTR_variant	Exon 6 of 9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.517C>T	p.Arg173Cys	missense_variant	Exon 6 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461008

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111498

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41326

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000895

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:5

Oct 18, 2017

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.517C>T (p.R173C) meets criteria to be classified as pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (Mester et al. 2018; manuscript in preparation). Please see a summary of the rules and criteria codes in the 'PTEN ACMG Specifications Summary' document (assertion method column). PS2_VS: At least two proven OR one proven plus two assumed de novo observations in a patient with the disease and no family history. (PMID 17526800, PMID 22628360, internal laboratory contributor(s) SCV000222220.10) PS3: Phosphatase activity <50% of wild type. (PMID 10866302) PM2: Absent in large sequenced populations (PMID 27535533). PS4_M: Probands with phenotype specificity score of 2-3.5. (PMID 22628360, PMID 17526800, PMID 17526801) PP1: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. (PMID 22628360) 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. -

Mar 28, 2024

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.517C>T variant in PTEN gene is located on the exon 6 and replaces arginine with cysteine at codon 173 of the PTEN protein (p.Arg173Cys). This variant has been observed in individuals with PTEN hamartoma tumor syndrome (PHTS) or Cowden syndrome (CS) (PMID:17526800, 22628360, 17526801, 24778394, 25669429, 21194675, 28526761). This variant has been reported to co-segregate with disease in one family (PMID: 22628360). In at least two individuals the variant was observed to be de novo (PMID:17526800, 22628360, 28526761). Experimental studies have shown that the variant eliminates the phosphatase activity of PTEN (PMID:10866302). Computational prediction tools (REVEL score 0.972) suggest that this variant may have deleterious impact on protein structure and function. This variant has been classified as pathogenic by multiple submitters including the ClinGen PTEN expert panel in ClinVar (ID: 189500). This variant is absent in the general population database according to gnomAD. Therefore, the c.517C>T (p.Arg173Cys) variant in the PTEN gene has been classified as pathogenic. -

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 173 of the PTEN protein (p.Arg173Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PTEN Hamartoma Tumor Syndrome (PMID: 17526800, 22628360, 24778394, 25669429). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189500). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PTEN function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302). For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2017

Herman Laboratory, Nationwide Children's Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2023

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PTEN c.517C>T (p.Arg173Cys) missense variant has been reported in a heterozygous state in at least six individuals with PTEN hamartoma tumor syndrome, including in four variably affected individuals from one family across two generations (PMID: 17526801; 17526800; 22628360). The variant is assumed to have occurred de novo in at least two affected individuals (PMID: 17526800; 22628360). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Studies of recombinant variant protein demonstrate that p.Arg173Cys results in a reduction in phosphatase activity when compared to wildtype (PMID: 10866302). This variant was identified in a de novo state. Based on the available evidence, the c.517C>T (p.Arg173Cys) variant is classified as pathogenic for PTEN hamartoma tumor syndrome. -

Cowden syndrome 1

Pathogenic:4

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]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 17526800, 22628360, 17526801, 24778394]. -

Jan 05, 2022

DASA

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.517C>T;p.(Arg173Cys) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:189500; PMID: 28526761; 28475857; 25669429; 25157968; 24778394; 17526800; 17526801; 22628360) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 10866302) - PS3_supporting. This variant is not present in population databases (rs121913293, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 428258) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 17526800; 22628360) - PM6. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Jul 12, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_x000D_ Criteria applied: PS3, PS4, PM1, PM5, PM2_SUP, PP3 -

Sep 26, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:4

Jun 01, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: absent or reduced phosphatase activity (Han 2000, Mighell 2018); Not observed 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: 17526800, 9635567, 29874181, 31006514, 32369273, 31216405, 10866302, 24778394, 22628360, 27481051, 9619835, 10746673, 10812170, 25669429, 28475857, 29663862, 20600018, 29706350, 26582918, 24475377, 33509259, 31594918, 30787465, 17526801) -

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 21, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PTEN c.517C>T (p.Arg173Cys) variant has been reported in the published literature in individuals with Cowden syndrome (PMIDs: 25669429 (2015), 21194675 (2011)), Bannayan-Riley-Ruvalcaba syndrome (PMIDs: 17526801 (2007), 17526800 (2007)), and PHTS-related breast cancer (PMIDs: 35931053 (2022), 24778394 (2014)). In three affected individuals this variant was reported to be de novo (PMIDs: 28526761 (2017), 22628360 (2012), 17526800 (2007)). An experimental study showed this variant caused significant loss of PTEN phosphatase activity in vitro (PMID: 10866302 (2000)). The frequency of this variant in the general population, 0.0000066 (1/151934 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Nov 11, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R173C pathogenic mutation (also known as c.517C>T), located in coding exon 6 of the PTEN gene, results from a C to T substitution at nucleotide position 517. The arginine at codon 173 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the literature in multiple individuals with clinical characteristics of Cowden syndrome or Cowden syndrome–like disease (Lachlan KL et al. J Med Genet, 2007 Sep;44:579-85; Tan WH et al. J Med Genet, 2007 Sep;44:594-602; Hopman SM et al. Am. J. Med. Genet. A, 2012 Jul;158A:1719-23; Ngeow J et al. J Clin Oncol, 2014 Jun;32:1818-24;.Tatton-Brown K et al. Am. J. Hum. Genet., 2017 May;100:725-736; Tang VT et al. Circ Genom Precis Med, 2018 01;11:e001966). This alteration has also been reported as de novo in individuals with clinical features of PTEN hamartoma tumor syndrome (PHTS) (Lachlan KL et al. J Med Genet, 2007 Sep;44:579-85; Hopman SM et al. Am. J. Med. Genet. A, 2012 Jul;158A:1719-23). In addition, one functional study demonstrated that the p.R173C mutant resulted in absent phosphatase activity (Han SY et al. Cancer Res, 2000 Jun;60:3147-51). 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. 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. -

Apr 20, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with cysteine at codon 173 of the PTEN protein. The amino acid residue is highly conserved in PTEN, a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. Functional studies have shown this variant to be defective for PTEN phosphatase activity (PMID: 10866302). This variant has been reported in individuals with clinical characteristics consistent with Cowden or Cowden-like syndrome (PMID: 17526800, 17526801, 21194675, 22628360, 24778394, 28475857, 28526761, 29874181), including two individuals in which it is assumed to have occurred de novo (PMID: 17526800, 28526761). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). -

not specified

Pathogenic:1

Feb 12, 2012

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Prostate cancer;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Pathogenic:1

Oct 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neurodevelopmental delay

Pathogenic:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Malignant lymphoma, large B-cell, diffuse

Pathogenic:1

Dec 04, 2023

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Post-initial therapy specimen. -

Glioma susceptibility 2

Pathogenic:1

Feb 07, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

VACTERL with hydrocephalus;C1854416:Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1

Pathogenic:1

Dec 31, 2017

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:-

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

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.0

PhyloP100

7.5

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.2

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

5.7

PromoterAI

-0.0052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.98

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over