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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN I306* variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genome fragility due to impaired chromosomal centromere association. This evidence supports a damaging effect of the PTEN I306* variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.02 | -70 bp |
| Donor Loss (DL) | 0.0 | 111 bp |
| Acceptor Gain (AG) | 0.0 | 179 bp |
| Donor Gain (DG) | 0.0 | 356 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. Modification Type: Disease-specific". The evidence for this variant shows: It is a truncating (nonsense) variant (I306*) in PTEN, a gene where loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant meets the conditions for a null variant leading to loss of function in PTEN.
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 OR different variant at same nucleotide position as a pathogenic splicing variant...". The evidence for this variant shows: This is a truncating variant, not a same-amino-acid missense change. 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 in a patient with the disease and no family history". The evidence for this variant shows: No de novo observations have been reported. Therefore, this criterion is not applied.
PS3 (Moderate)
According to PTEN Pre-processing, the finding for PS3 is: "Applied PS3_Moderate evidence based on high-confidence functional score (-3.5854) < threshold (-1.11)". The evidence for this variant shows: Well-established in vitro functional studies demonstrate loss of PTEN phosphatase activity and increased oncogenicity. Therefore, this criterion is applied at Moderate strength because the functional data meet the PTEN-specific threshold for PS3_Moderate.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Moderate strength for 2–3.5 probands; Strong for 4–15.5; Very Strong for ≥16 with specificity score". The evidence for this variant shows: No proband count or case-control 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 and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168)". The evidence for this variant shows: Position I306 is outside the defined catalytic motifs. 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 found in gnomAD or other large population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant". The evidence for this variant shows: PTEN-related disease is autosomal dominant and no trans observations are relevant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: This is a frameshift leading to a premature stop, 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 a residue where a different pathogenic missense has been seen". The evidence for this variant shows: This is a truncating variant, not a missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Moderate Assumed de novo without paternity/maternity confirmation". The evidence for this variant shows: No de novo status reported. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong co-segregation in multiple affected family members". The evidence for this variant shows: No family 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 benign variation where missense is common mechanism". The evidence for this variant shows: This is a truncating variant, not a missense. 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: Computational predictions are insufficient; SpliceAI score is low. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Phenotype specificity for disease with single genetic etiology". The evidence for this variant shows: No detailed patient phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic". The evidence for this variant shows: Not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone 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 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 homozygous in healthy individual". 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 damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong lack of segregation in multiple families". 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 gene where truncating variants are common mechanism". The evidence for this variant shows: This is a truncating variant, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting Observed in trans with pathogenic variant or in cis with multiple pathogenic variants". The evidence for this variant shows: No such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting In-frame indel in repetitive region". The evidence for this variant shows: This is a frameshift truncation, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting Computational evidence suggests no impact". The evidence for this variant shows: Although computational splicing predicts minimal impact, the variant is truncating causing loss-of-function. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Supporting Variant found with alternate molecular basis". The evidence for this variant shows: No alternate genetic explanation 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: Not reported as benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "Supporting Synonymous or intronic variant with no splicing impact". The evidence for this variant shows: It is a truncating coding variant. Therefore, this criterion is not applied.