10-87960892-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePP3_StrongPP5_Very_Strong

The NM_000314.8(PTEN):c.802-2A>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

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

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 8.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.09240924 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 43, new splice context is: aaatacattcttcataccAGgac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 10-87960892-A-T is Pathogenic according to our data. Variant chr10-87960892-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 142423.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr10-87960892-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
PTEN	NM_000314.8 linkuse as main transcript	c.802-2A>T	splice_acceptor_variant	ENST00000371953.8
PTEN	NM_001304717.5 linkuse as main transcript	c.1321-2A>T	splice_acceptor_variant
PTEN	NM_001304718.2 linkuse as main transcript	c.212-2A>T	splice_acceptor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTEN	ENST00000371953.8 linkuse as main transcript	c.802-2A>T		splice_acceptor_variant		1	NM_000314.8	P1	P60484-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

119978

Hom.:

Cov.:

FAILED QC

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

GnomAD3 exomes

AF:

0.0000507

AC:

AN:

177630

Hom.:

AF XY:

0.0000512

AC XY:

AN XY:

97728

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.0000394

Gnomad4 AMR exome

AF:

0.000237

Gnomad4 ASJ exome

AF:

0.000140

Gnomad4 EAS exome

AF:

0.000122

Gnomad4 SAS exome

AF:

0.0000798

Gnomad4 FIN exome

AF:

0.000282

Gnomad4 NFE exome

AF:

0.0000994

Gnomad4 OTH exome

AF:

0.000104

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

Gnomad4 AFR

AF:

0.0000309

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000297

Gnomad4 NFE

AF:

0.0000355

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

PTEN hamartoma tumor syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 14, 2023	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. 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. Disruption of this splice site has been observed in individuals with Cowden syndrome (PMID: 27477328, 28677221; Invitae). ClinVar contains an entry for this variant (Variation ID: 142423). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Clingen PTEN Variant Curation Expert Panel, Clingen	Oct 18, 2017	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 11, 2019	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

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	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) -

Cowden syndrome 1

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Cancer Genomic Medicine Translational Research Lab, Cleveland Clinic Genomic Medicine Institute	May 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

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

Dann

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

GERP RS

5.1

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

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