Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenFor these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant has been observed in an individual with clinical features of PTEN hamartoma tumor syndrome (PMID: 21194675). ClinVar contains an entry for this variant (Variation ID: 189489). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu150*) in the PTEN gene. It is expected to result in an absent or disrupted protein product.
"This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN E150* variant is a truncating mutation that results in a premature stop codon, leading to the production of a truncated PTEN protein. Functional studies indicate that this truncation results in a loss of PTEN phosphatase activity, as demonstrated by reduced activity in a yeast assay. Additionally, expression of similar truncating mutations in mouse embryonic fibroblasts has shown oncogenic properties, including increased genome fragility and impaired regulation of the PI3K/AKT pathway. These findings support the conclusion that the PTEN E150* variant has a damaging effect on protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.04 | -212 bp |
| Donor Loss (DL) | 0.02 | 44 bp |
| Acceptor Gain (AG) | 0.0 | 3 bp |
| Donor Gain (DG) | 0.0 | -78 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Use PTEN PVS1 decision tree.' The evidence for this variant shows: a truncating (nonsense) variant in PTEN where loss of function is a known mechanism and it is not located in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant meets the PTEN PVS1 decision tree for null variants.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: no different nucleotide change resulting in the same E150* has been reported. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations.' The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3 (Moderate)
According to PTEN Pre-processing, the finding for PS3 is: 'PS3_Moderate evidence added based on high-confidence functional score (-3.9486) < threshold (-1.11).' The evidence for this variant shows: phosphatase activity score of -3.9486 in a yeast assay indicating damaging effect. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN PS3 threshold.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Strong prevalence in affected individuals or specificity score 4-15.5.' The evidence for this variant shows: no case or specificity score data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Moderate Located in a mutational hot spot or critical domain including residues 90-94, 123-130, 166-168.' The evidence for this variant shows: E150 is outside defined PTEN hotspot residues. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Absent in population Databases present at <0.00001 allele frequency in gnomAD.' The evidence for this variant shows: not observed in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'Moderate Detected in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: PTEN-related disease is autosomal dominant, no trans data. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Moderate Protein length changes due to in-frame insertions/deletions or stop-loss variants.' The evidence for this variant shows: it is a nonsense, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Moderate Missense change at an amino acid residue where a different missense change is pathogenic.' The evidence for this variant shows: it is a nonsense variant, not a missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: 'Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations.' The evidence for this variant shows: no assumed de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Supporting Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Supporting Missense variant in gene with low rate of benign missense variation.' The evidence for this variant shows: it is a nonsense variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows: it is a nonsense variant and computational predictors are not relevant. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.' The evidence for this variant shows: no phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Reputable source reports variant as pathogenic but evidence not available for independent evaluation.' The evidence for this variant shows: ClinVar lists this variant as Pathogenic by three clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone gnomAD Filtering allele frequency >0.00056.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Strong gnomAD Filtering allele frequency 0.000043–0.00056.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong Observed in homozygous state in healthy individuals.' The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Strong Functional studies show no damaging effect.' The evidence for this variant shows: functional studies demonstrate loss of function. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Strong Lack of segregation in affected members.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: 'Supporting Missense variant in a gene where only truncating variants cause disease.' The evidence for this variant shows: it is truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Supporting Observed in trans with a pathogenic variant for recessive disorders.' The evidence for this variant shows: no trans data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule for BP3 is: 'Supporting In-frame indels in repetitive regions.' The evidence for this variant shows: not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: computational tools are not relevant to a nonsense variant. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: 'Supporting Variant found in a case with an alternate molecular basis for disease.' The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Reputable source reports variant as benign.' The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting Synonymous or intronic variant with no splicing impact.' The evidence for this variant shows: it is nonsense. Therefore, this criterion is not applied.