rs587782455
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000314.8(PTEN):c.802-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 30)
Exomes 𝑓: 0.0000017 ( 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 16 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.
PM2
?
Very rare variant in population databases, with high coverage;
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-G is Pathogenic according to our data. Variant chr10-87960892-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 189509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-87960892-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.802-2A>G | splice_acceptor_variant | ENST00000371953.8 | |||
PTEN | NM_001304717.5 | c.1321-2A>G | splice_acceptor_variant | ||||
PTEN | NM_001304718.2 | c.212-2A>G | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.802-2A>G | splice_acceptor_variant | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 30
GnomAD3 genomes
?
Cov.:
30
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000173 AC: 2AN: 1156364Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 577792
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
2
AN:
1156364
Hom.:
Cov.:
34
AF XY:
AC XY:
0
AN XY:
577792
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 30
GnomAD4 genome
?
Cov.:
30
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
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 hamartoma tumor syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 189509). Disruption of this splice site has been observed in individuals with Cowden syndrome (PMID: 27477328, 28677221). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 7 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2018 | The c.802-2A>G variant in PTEN has been reported in 1 individual with Cowden syndrome (a sub-type of PTEN hamartoma tumor syndrome; Chen 2017) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence. Functional studies suggest that the variant causes altered splicing leading to an abnormal or absent protein (Chen 2017). Heterozygous loss-of-function of the PTEN gene is an established disease mechanism in individuals with PTEN hamartoma tumor syndrome. In summary, this variant is pathogenic for PTEN hamartoma tumor syndrome in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1; PM2; PP4. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PTEN: PVS1, PM2, PS3:Supporting, PS4:Supporting - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 17, 2020 | The c.802-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 8 in the PTEN gene. This variant has been reported in individuals diagnosed with Cowden syndrome (Chen HH et al. J. Allergy Clin. Immunol., 2017 02;139:607-620.e15; Chen HJ et al. Hum. Mutat., 2017 10;38:1372-1377). In addition, 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). A different pathogenic mutation at the same nucleotide position, c.802-2A>T, has been identified in individuals diagnosed with Cowden syndrome and results in the same splicing defect (Ambry internal data; Chen HJ et al. Hum. Mutat., 2017 10;38:1372-1377). 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. 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