chr10-87960892-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
NM_000314.8 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 8.81
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]
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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 | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.802-2A>T | splice_acceptor_variant | ENST00000371953.8 | |||
PTEN | NM_001304717.5 | c.1321-2A>T | splice_acceptor_variant | ||||
PTEN | NM_001304718.2 | c.212-2A>T | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.802-2A>T | splice_acceptor_variant | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 5AN: 119978Hom.: 0 Cov.: 30 FAILED QC
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GnomAD3 exomes AF: 0.0000507 AC: 9AN: 177630Hom.: 0 AF XY: 0.0000512 AC XY: 5AN XY: 97728
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000110 AC: 127AN: 1155290Hom.: 0 Cov.: 34 AF XY: 0.000106 AC XY: 61AN XY: 577280
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GnomAD4 genome ? Data not reliable, filtered out with message: AS_VQSR AF: 0.0000417 AC: 5AN: 120000Hom.: 0 Cov.: 30 AF XY: 0.0000520 AC XY: 3AN XY: 57696
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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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 45
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at