10-87957955-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP2PS4PM2PS2

This summary comes from the ClinGen Evidence Repository: PTEN c.737C>T (p.P246L) 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 23934111, internal laboratory contributor(s) SCV000222227.10)PS4: Probands with phenotype specificity score of 4-15.5. (PMID 24375884, PMID 10076877, PMID 22261759, PMID 23934111, internal laboratory contributor(s) SCV000222227.10)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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA000559/MONDO:0017623/003

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 7.51

Publications

64 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 11 ACMG points.

PS2

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 rank	MANE	Protein
PTEN	NM_000314.8 link	c.737C>T	p.Pro246Leu	missense_variant	Exon 7 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.1256C>T	p.Pro419Leu	missense_variant	Exon 8 of 10		NP_001291646.4
PTEN	NM_001304718.2 link	c.146C>T	p.Pro49Leu	missense_variant	Exon 7 of 9		NP_001291647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.737C>T	p.Pro246Leu	missense_variant	Exon 7 of 9	1	NM_000314.8	ENSP00000361021.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111960

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Cov.:

Alfa

AF:

0.00

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cowden syndrome 1

Pathogenic:5

Apr 05, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29785012, 32350270]. -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 05, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 03, 2017

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This c.737C>T (p.Pro246Leu) variant was detected in 3 members of a family with Bannayan-Riley-Ruvalcaba syndrome (BRRS) [PMID 10400993]. BRRS is allelic to Cowden syndrome and is characterized by macrocephaly, hamartomatous intestinal polyposis, lipomas, and pigmented macules of the glans penis. The variant was further detected de novo in a cohort of 264 trio diagnosed with seizure. The patient had infantile spasms in addition to vascular anomalies and macrocephaly [PMID 23934111]. We have observed this variant, de novo, in a patient with autism in our internal database. This c.737C>T (p.Pro246Leu) variant was not observed in the gnomAD population database. Proline at amino acid position 246 is conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen2 predict this p.Pro246Leu to be deleterious. This variant is thus classified as pathogenic. -

Mar 07, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Pathogenic:5

Apr 16, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PTEN c.737C>T (p.Pro246Leu) variant has been reported in the published literature in individuals meeting Cownden syndrome diagnostic criteria (PMIDs: 27477328 (2017), 24375884 (2014), 22261759 (2012)). This variant has been identified as a de novo occurrence in an individual with epileptic encephalopathies (PMID: 23934111 (2013)). Functional evidence suggests that this variant may impact protein function (PMIDs: 23934111 (2013), 21828076 (2011), 14566704 (2003)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Feb 22, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple unrelated patients with features of PTEN Hamartoma Tumor syndrome referred for genetic testing at GeneDx and in published literature (Marsh 1999, Zhou 2003, Hobert 2012, Vanderver 2014); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect: partial loss of phosphastase activity and protein instability (Andres-Pons 2007, Rodriguez-Escudero 2011, Mighell 2018, Matreyek 2018); 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: 27477328, 10923032, 26681312, 10076877, 17942903, 25669429, 23934111, 12938083, 21194675, 14566704, 25527629, 23161105, 14518068, 24744697, 22261759, 24375884, 10400993, 15805158, 27146902, 30555518, 28152038, 28263302, 30174244, 31336731, 31046523, 21828076, 29706350, 31447099, 32162695, 33726816, 18626510) -

PTEN hamartoma tumor syndrome

Pathogenic:4

Oct 18, 2017

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.737C>T (p.P246L) 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 23934111, internal laboratory contributor(s) SCV000222227.10) PS4: Probands with phenotype specificity score of 4-15.5. (PMID 24375884, PMID 10076877, PMID 22261759, PMID 23934111, internal laboratory contributor(s) SCV000222227.10) 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. -

May 24, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro246Leu variant in PTEN has been reported in at least 3 individuals with PTEN-associated phenotypes: 1 with Bannayan-Riley-Ruvalcaba syndrome (BRRS), 1 with Lhermitte-Duclos disease (LDD), and 1 with colon cancer and segregated with BRRS in 2 affected relatives (Marsh 1999, Otto 1999, Zhou 2003, Hobert 2012, Su sswein 2016). In addition, it was reported as a de novo occurrence in an infant with infantile spasms and clinical features of a PTEN hamartoma tumor syndrome ( Allen 2013). Functional studies provide some evidence that the p.Pro246Leu varia nt is associated with decreased protein activity (Rodriguez-Escudero 2011). This variant was absent from large population studies. In summary, although addition al studies are required to fully establish its clinical significance, the p.Pro2 46Leu variant is likely pathogenic. -

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 246 of the PTEN protein (p.Pro246Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with symptoms consistent with PTEN hamartoma tumor syndrome (PHTS) (PMID: 10076877, 22261759, 23934111, 24375884, 27477328). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as chr10:89717712 C>T. ClinVar contains an entry for this variant (Variation ID: 142269). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTEN protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PTEN function (PMID: 14566704, 17942903, 21828076). For these reasons, this variant has been classified as Pathogenic. -

May 26, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (PTEN C2 domain; NCBI). (N) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple patients with PTEN hamartoma tumor syndrome and Cowden syndrome (ClinVar, PMID: 27477328). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies in yeast cells demonstrated partially impaired phosphatase activity (PMID: 21828076). (P) 1204 - Variant shown to be de novo in proband (parental status not tested but assumed). (P) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Breast and/or ovarian cancer

Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Macrocephaly-autism syndrome;C2751642:Glioma susceptibility 2;C2931456:Familial prostate cancer;C3551915:Familial meningioma;CN072330:Cowden syndrome 1

Pathogenic:1

Apr 20, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Gastric cancer

Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 11, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.737C>T (p.P246L) alteration is located in exon 7 (coding exon 7) of the PTEN gene. This alteration results from a C to T substitution at nucleotide position 737, causing the proline (P) at amino acid position 246 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported as heterozygous in multiple individuals who met clinical criteria for PTEN hamartoma tumor syndrome, and was determined to be the result of a de novo mutation in one individual (Hobert, 2012; Vanderver, 2014; Shao, 2020). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). A yeast-based assay demonstrated that this alteration combined with another missense alteration failed to rescue yeast cells from p110alpha CAAX induced growth inhibition and release GFP-AKt1 from the cellular membrane, although both alterations by themselves had similar activity to wildtype. The authors postulated that this assay suggests patient-dependent loss of function effects (Andrés-Pons, 2007). In addition, p.P246L has been described as a pathogenic mutation leading to impaired PTEN protein levels and signaling in Lhermitte-Dulcose disease cells (Zhou, 2003). In another functional assay, this variant demonstrated low intracellular protein abundance on one multiplex functional assay (Matreyek, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Macrocephaly-autism syndrome

Pathogenic:1

Jul 23, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.86

D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

0.024

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

7.5

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.014

D;.

Sift4G

Benign

0.36

T;T

Polyphen

0.73

P;.

Vest4

0.96

MutPred

0.63

Loss of sheet (P = 0.0357);.;

MVP

0.99

MPC

1.3

ClinPred

0.99

GERP RS

5.2

Varity_R

0.45

gMVP

0.92

Mutation Taster

=5/95

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over