10-87960892-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS4_SupportingPVS1PM2

This summary comes from the ClinGen Evidence Repository: PTEN c.802-2A>T (IVS7-2A>T) 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).PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5’ to c.1121 (NM_000314.4).PM2: Absent in large sequenced populations (PMID 27535533).PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s), SCV000222230.9) LINK:https://erepo.genome.network/evrepo/ui/classification/CA000591/MONDO:0017623/003

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PTEN
NM_000314.8 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 8.81

Publications

18 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.

PVS1

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
PTEN	NM_000314.8 link	c.802-2A>T	splice_acceptor_variant, intron_variant	Intron 7 of 8	ENST00000371953.8	NP_000305.3
PTEN	NM_001304717.5 link	c.1321-2A>T	splice_acceptor_variant, intron_variant	Intron 8 of 9		NP_001291646.4	P60484
PTEN	NM_001304718.2 link	c.211-2A>T	splice_acceptor_variant, intron_variant	Intron 7 of 8		NP_001291647.1	P60484

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTEN	ENST00000371953.8 link	c.802-2A>T		splice_acceptor_variant, intron_variant	Intron 7 of 8	1	NM_000314.8	ENSP00000361021.3		P60484-1

Frequencies

GnomAD3 genomes

AF:

0.0000417

AC:

AN:

119978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000310

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:

0.000297

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000355

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000507

AC:

AN:

177630

AF XY:

0.0000512

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000136

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000195

Gnomad FIN exome

AF:

0.000171

Gnomad NFE exome

AF:

0.0000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000110

AC:

127

AN:

1155290

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

577280

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000394

AC:

AN:

25380

American (AMR)

AF:

0.000237

AC:

AN:

29534

Ashkenazi Jewish (ASJ)

AF:

0.000140

AC:

AN:

21466

East Asian (EAS)

AF:

0.000122

AC:

AN:

32668

South Asian (SAS)

AF:

0.0000798

AC:

AN:

62680

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

46110

Middle Eastern (MID)

AF:

0.000223

AC:

AN:

4478

European-Non Finnish (NFE)

AF:

0.0000994

AC:

AN:

885078

Other (OTH)

AF:

0.000104

AC:

AN:

47896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.252

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000417

AC:

AN:

120000

Hom.:

Cov.:

AF XY:

0.0000520

AC XY:

AN XY:

57696

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000309

AC:

AN:

32376

American (AMR)

AF:

0.00

AC:

AN:

11440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2906

East Asian (EAS)

AF:

0.00

AC:

AN:

3610

South Asian (SAS)

AF:

0.00

AC:

AN:

3890

European-Finnish (FIN)

AF:

0.000297

AC:

AN:

6726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

192

European-Non Finnish (NFE)

AF:

0.0000355

AC:

AN:

56390

Other (OTH)

AF:

0.00

AC:

AN:

1648

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.245

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:3

Oct 18, 2017

Clingen PTEN Variant Curation Expert Panel, Clingen

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

PTEN c.802-2A>T (IVS7-2A>T) 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). PVS1: Null variant predicted to result in nonsense-mediated decay or causing truncation/frameshift at or 5' to c.1121 (NM_000314.4). PM2: Absent in large sequenced populations (PMID 27535533). PS4_P: Proband(s) with phenotype specificity score of 1-1.5. (Internal laboratory contributor(s), SCV000222230.9) -

Sep 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Disruption of this splice site has been observed in individuals with Cowden syndrome (PMID: 27477328, 28677221; Invitae). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects an acceptor splice site in intron 7 of the PTEN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 28677221; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 142423). -

Dec 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.802-2A>T variant in PTEN has been reported in 1 individual with Cowden syndrome (Nizialek 2015). It has also been identified in 0.02% (2/11304) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org).This variant was classified as Pathogenic on 10/18/17 by the ClinGen-approved PTEN variant curation expert panel (Variation ID: 142423). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss-of-function of the PTEN gene is an established disease mechanism in individuals with PTEN hamartoma tumor syndrome. In summary, this variant meets our criteria to be classified as pathogenic for PTEN hamartoma tumor syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting. -

not provided

Pathogenic:3

Oct 24, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Chen et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28677221, 25669429, 22005521, 28152038, 30311380, 32710294, 33258288, 36453251) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: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

- -

Cowden syndrome 1

Pathogenic:2

May 26, 2017

Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

May 10, 2023

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28677221, 28013114]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 28677221]. -

PTEN-related disorder

Pathogenic:1

Jul 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PTEN c.802-2A>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in individuals with PTEN hamartoma tumor syndrome (PHTS; Table S4, Nizialek et al. 2015. PubMed ID: 25669429; Table 1, Wang et al. 2022. PubMed ID: 36453251). This variant is reported in 0.018% of alleles in individuals of East Asian descent in gnomAD. It is interpreted as pathogenic by the ClinGen PTEN Variant Curation Expert Panel in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/142423/). Variants that disrupt the consensus splice acceptor site in PTEN are expected to be pathogenic. An alternate A-to-G nucleotide change at this acceptor site has been reported to be associated with PHTS (Table 1, Chen et al. 2017. PubMed ID: 28677221; https://preview.ncbi.nlm.nih.gov/clinvar/variation/189509/). The c.802-2A>T variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

May 23, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.802-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 8 in the PTEN gene. This alteration segregated with disease in one PTEN hamartoma tumor syndrome (PHTS) family tested at our laboratory (Ambry internal data). This mutation has also been detected in cohorts of patients who met clinical diagnostic criteria for Cowden syndrome (CS) or relaxed clinical diagnostic criteria for CS-like (Nizialek EA et al. Eur. J. Hum. Genet. 2015 Nov;23:1538-43; Chen HJ et al. Hum. Mutat., 2017 10;38:1372-1377). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. RNA studies have demonstrated that this variant results in abnormal splicing with out-of-frame deletion of 43 nucleotides from the beginning of coding exon 8 through use of a cryptic acceptor site (Ambry internal data; Chen HJ et al. Hum. Mutat., 2017 10;38:1372-1377). As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

1.0

PhyloP100

8.8

GERP RS

5.1

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.88

Position offset: 45

DS_AL_spliceai

1.0

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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10-87960892-A-T

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