10-87952142-C-T

Position:

chr10-87952142-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PS2PP2PP1PS4_ModeratePS3

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

17

1

1

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 7.46

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:

PTEN (HGNC:):

PTEN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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/exons	MANE	Protein	UniProt
PTEN	NM_000314.8 linkuse as main transcript	c.517C>T	p.Arg173Cys	missense_variant	6/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1036C>T	p.Arg346Cys	missense_variant	7/10		NP_001291646.4	P60484
PTEN	NM_001304718.2 linkuse as main transcript	c.-75C>T		5_prime_UTR_variant	6/9		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.517C>T	p.Arg173Cys	missense_variant	6/9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

1

AN:

151934

Hom.:

0

Cov.:

32

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:

4

AN:

1461008

Hom.:

0

Cov.:

31

AF XY:

0.00000275

AC XY:

2

AN XY:

726858

show subpopulations

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

1

AN:

151934

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000454

Hom.:

0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:5

Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 18, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Herman Laboratory, Nationwide Children's Hospital	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Mar 28, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 14, 2024	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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 08, 2023	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:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 12, 2022	_x000D_ Criteria applied: PS3, PS4, PM1, PM5, PM2_SUP, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 28, 2023	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]. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2022	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 20, 2021	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 11, 2024	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. -

not specified

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

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

Feb 12, 2012

- -

Neurodevelopmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

-

- -

Malignant lymphoma, large B-cell, diffuse

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department Of Pathology & Laboratory Medicine, University Of Pennsylvania

Dec 04, 2023

Post-initial therapy specimen. -

Malignant tumor of prostate;C1854416:Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 20, 2021

- -

Glioma susceptibility 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 07, 2023

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 31, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

D

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

34

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Pathogenic

1.0

D

M_CAP

Pathogenic

0.82

D

MetaRNN

Pathogenic

0.97

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

4.0

H

PrimateAI

Pathogenic

0.92

D

PROVEAN

Pathogenic

-7.2

D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.99

MVP

0.99

MPC

2.6

ClinPred

1.0

D

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.98

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: rs121913293; hg19: chr10-89711899; COSMIC: COSV64288569; COSMIC: COSV64288569;