10-87925550-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000314.8(PTEN):c.202T>C(p.Tyr68His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,424,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y68?) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PTEN
NM_000314.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 7.42

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 Pathogenic. Variant got 19 ACMG points.

PM1

In a strand (size 8) in uniprot entity PTEN_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000314.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-87925550-TAC-TT is described in Lovd as [Pathogenic].

PP2

Missense variant in the PTEN gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 209 curated pathogenic missense variants (we use a threshold of 10). The gene has 22 curated benign missense variants. Gene score misZ: 3.4883 (above the threshold of 3.09). Trascript score misZ: 4.1129 (above the threshold of 3.09). GenCC associations: The gene is linked to Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, macrocephaly-autism syndrome, Cowden syndrome 1, Cowden disease, Proteus-like syndrome, leiomyosarcoma, activated PI3K-delta syndrome, PTEN hamartoma tumor syndrome, glioma susceptibility 2, renal cell carcinoma.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 10-87925550-T-C is Pathogenic according to our data. Variant chr10-87925550-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87925550-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.202T>C	p.Tyr68His	missense_variant	Exon 3 of 9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.721T>C	p.Tyr241His	missense_variant	Exon 4 of 10		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.-541-5496T>C		intron_variant	Intron 2 of 8		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.202T>C	p.Tyr68His	missense_variant	Exon 3 of 9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1424326

Hom.:

Cov.:

AF XY:

0.00000141

AC XY:

AN XY:

709980

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:

0.00000184

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cowden syndrome 1

Pathogenic:3

Mar 17, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9467011, 9600246, 20926450]. Functional studies indicate this variant impacts protein function [PMID: 10866302]. -

Aug 16, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macrocephaly-autism syndrome

Pathogenic:2

Oct 25, 2022

Eurofins-Biomnis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PTEN hamartoma tumor syndrome

Pathogenic:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 68 of the PTEN protein (p.Tyr68His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Cowden syndrome (PMID: 9467011, 9600246, 19457929, 20926450, 25288137, 25669429, 25722288). ClinVar contains an entry for this variant (Variation ID: 189474). 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 expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PTEN function (PMID: 10866302, 19457929, 20926450). This variant disrupts the p.Tyr68 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19457929, 21956414, 24778394, 26246517). 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:1

Oct 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency 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: 29970488, 26246517, 19457929, 25669429, 20926450, 9467011, 21659347, 25722288, 11494117, 10400993, 9600246, 24778394, 21956414, 31055886, 29706350, 25288137, 24475377, 30787465, 29152901, 31006514, 36591942, 36453251, 36747841, 32588888, 32127467, 33153119, 29663862, 32665702, 33087929, 37781577, 10866302) -

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

Pathogenic:1

Nov 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jul 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y68H pathogenic mutation (also known as c.202T>C), located in coding exon 3 of the PTEN gene, results from a T to C substitution at nucleotide position 202. The tyrosine at codon 68 is replaced by histidine, an amino acid with similar properties. This variant has been identified in individuals meeting clinical diagnostic criteria for Bannayan-Zonana syndrome and Cowden syndrome (Marsh DJ. Hum Mol Genet. 1998 Mar;7(3):507-15; Tsou HC et al. Hum. Genet. 1998 Apr;102:467-73; Lobo, GP. Hum Mol Genet. 2009 Aug 1;18(15):2851-62; Cooiman MI et al. Mol Genet Genomic Med. 2019 Jun;7:e00632), and another proband with suspected PTEN hamartoma tumor syndrome (PHTS) (Pilarski, R. J Med Genet. 2011 Aug;48(8):505-12). This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with PHTS (Ambry internal data). Functional and structural analyses have demonstrated that this variant produces no phosphatase activity and impairs PTEN protein function, localization and stability (Georgescu MM et al. Cancer Res. 2000 Dec;60:7033-8; Han SY et al. Cancer Res. 2000 Jun;60:3147-51; Lobo, GP. Hum Mol Genet. 2009 Aug 1;18(15):2851-62; He X. Hum Mol Genet. 2011 Jan 1;20(1):80-9; Matreyek KA et al. Nat. Genet. 2018 06;50:874-882; Smith IN et al. J. Biomol. Struct. Dyn. 2019 Apr;37:1766-1782; Smith IN et al. Am. J. Hum. Genet. 2019 May;104:861-878; Mighell TL et al. Am J Hum Genet. 2018 05;102:943-955). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Glioma susceptibility 2

Pathogenic:1

May 28, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Macrocephaly-autism syndrome;CN072330:Cowden syndrome 1

Other:1

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 01-13-2021 by Lab Prevention Genetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.80

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.8

REVEL

Pathogenic

0.99

Sift

Uncertain

0.018

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.93

Gain of disorder (P = 0.0256);

MVP

0.99

MPC

2.6

ClinPred

1.0

GERP RS

5.5

Varity_R

0.88

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over