chr10-87960914-G-A

Position:

chr10-87960914-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000314.8(PTEN):c.822G>A(p.Trp274*) variant causes a stop gained change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.56

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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 10-87960914-G-A is Pathogenic according to our data. Variant chr10-87960914-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 142640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87960914-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTEN	NM_000314.8 linkuse as main transcript	c.822G>A	p.Trp274*	stop_gained	8/9	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 linkuse as main transcript	c.1341G>A	p.Trp447*	stop_gained	9/10		NP_001291646.4	P60484
PTEN	NM_001304718.2 linkuse as main transcript	c.231G>A	p.Trp77*	stop_gained	8/9		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.822G>A	p.Trp274*	stop_gained	8/9	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

146144

Hom.:

Cov.:

FAILED QC

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000206

AC:

AN:

1454488

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723226

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:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000684

AC:

AN:

146144

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

70840

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:

0.0000150

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cowden syndrome 1

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 02, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Provincial Medical Genetics Program of British Columbia, University of British Columbia	Jan 01, 2022	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25737639, 21659347, 28152038, 25549896) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 06, 2023	The PTEN c.822G>A (p.Trp274*) variant causes the premature termination of PTEN protein synthesis. This variant has been reported in the published literature in an individual with clinical features suggestive of PTEN hamartoma tumor syndrome (PHTS) (PMID: 21659347 (2011)). 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. -

PTEN-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 20, 2023

The PTEN c.822G>A variant is predicted to result in premature protein termination (p.Trp274*). This variant has been reported in individuals with PTEN hamartoma tumor syndrome (Pilarski et al. 2011. PubMed ID: 21659347; LaDuca et al. 2017. PubMed ID: 28152038). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in PTEN are expected to be pathogenic. This variant is interpreted as pathogenic. -

PTEN hamartoma tumor syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 30, 2023

This sequence change creates a premature translational stop signal (p.Trp274*) in the PTEN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with PTEN hamartoma tumor syndrome (PMID: 21659347). ClinVar contains an entry for this variant (Variation ID: 142640). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2024

The p.W274* pathogenic mutation (also known as c.822G>A) located in coding exon 8 of the PTEN gene, results from a G to A substitution at nucleotide position 822. This changes the amino acid from a tryptophan to a stop codon within coding exon 8. This alteration and a separate nucleotide change (c.821G>A) resulting in protein truncation at the same position have both been identified in patients with features consistent with PTEN hamartoma tumor syndrome (PHTS) (Pilarski R et al. J. Med. Genet. 2011; 48:505-12; Pilarksi R, personal communication; Busa T et al. Eur. J. Paediatr. Neurol. 2015 Mar;19:188-92; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

Vest4

0.94

GERP RS

5.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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