chr10-87894038-CATT-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4_SupportingPP3PP5_Very_Strong
The NM_000314.8(PTEN):c.97_99del(p.Ile33del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I32I) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
PTEN
NM_000314.8 inframe_deletion
NM_000314.8 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.54
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.
PM1
?
In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000314.8
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_000314.8. Strenght limited to Supporting due to length of the change: 1aa.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 10-87894038-CATT-C is Pathogenic according to our data. Variant chr10-87894038-CATT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449088.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTEN | NM_000314.8 | c.97_99del | p.Ile33del | inframe_deletion | 2/9 | ENST00000371953.8 | |
PTEN | NM_001304717.5 | c.616_618del | p.Ile206del | inframe_deletion | 3/10 | ||
PTEN | NM_001304718.2 | c.-609_-607del | 5_prime_UTR_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTEN | ENST00000371953.8 | c.97_99del | p.Ile33del | inframe_deletion | 2/9 | 1 | NM_000314.8 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
PTEN hamartoma tumor syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely pathogenic, reviewed by expert panel | curation | Clingen PTEN Variant Curation Expert Panel, Clingen | Aug 04, 2023 | PTEN c.97_99delATT (c.94ATT[1]) (p.Ile33del) meets criteria to be classified as likely pathogenic for PTEN Hamartoma Tumor syndrome in an autosomal dominant manner using modified ACMG criteria (ACMG Classification Rules Specified for PTEN Variant Curation version 3.0.0). Please see a summary of the rules and criteria codes in the “PTEN ACMG Specifications Summary” document (assertion method column). PS3_Moderate: Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. PM2_Supporting: Absent in large sequenced populations (PMID 27535533). PM6_Strong: An individual with a highly specific phenotype (Internal laboratory contributor SCV000616838.1). PP1: Co-segregation with disease in multiple affected family members, with 5 or 6 meioses observed. (PMID 10234502 , internal laboratory contributor SCV002559099.1) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This variant, c.97_99del, results in the deletion of 1 amino acid(s) of the PTEN protein (p.Ile33del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with features of Bannayan-Riley-Ruvalcaba syndrome or adult-onset Lhermitte-Duclos disease and Cowden syndrome (PMID: 10234502; Invitae; external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 449088). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Likely 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 | GeneDx | Feb 07, 2022 | In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate a damaging effect: significantly reduced lipid phosphatase activity in a high-throughput assay (Mighell 2018); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21194675, 18558293, 10923032, 23674493, 9765621, 30325992, 33163849, 31594918, 10234502, 29706350, 24475377) - |
Neurodevelopmental delay Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2022 | The c.97_99delATT variant (also known as p.I33del) is located in coding exon 2 of the PTEN gene. This variant results from an in-frame ATT deletion at nucleotide positions 97 to 99. This results in the in-frame deletion of an isoleucine at codon 33. This alteration has been reported in multiple individuals with PTEN hamartoma tumor syndrome (Ambry internal data; Nelen MR et al. Eur. J. Hum. Genet., 1999 Apr;7:267-73; Busch RM et al. Transl Psychiatry, 2019 10;9:253). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 05;102:943-955). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Lee CU et al. Angew Chem Int Ed Engl, 2015 Nov;54:13796-800). The deleted amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
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SpliceAI score (max)
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