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"This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN N69Ifs*30 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that this truncation is oncogenic, increasing genome fragility due to impaired chromosomal centromere association.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -5 bp |
| Donor Loss (DL) | 0.02 | 9 bp |
| Acceptor Gain (AG) | 0.01 | -39 bp |
| Donor Gain (DG) | 0.0 | 5 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines (PVS1 Decision Tree for PTEN), the rule for PVS1 is: 'Null Variant (nonsense, frameshift, etc.) in a gene where loss of function is a known mechanism of disease' at Very Strong strength. The evidence for this variant shows: c.206delA causes a frameshift resulting in a premature stop (N69Ifs*30) not in the last exon of PTEN. Therefore, this criterion is applied at Very Strong strength because it is a truncating LOF variant in PTEN.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: '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, where in silico models predict impact equal to or greater than the known pathogenic variant.' The evidence for this variant shows: N69Ifs*30 is a frameshift, not the same amino acid substitution as any known pathogenic variant. Therefore, this criterion is not applied because the variant does not meet the rule.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) occurrence in a patient with the disease and no family history' at Strong strength. The evidence for this variant shows: no de novo data or parental confirmation are available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.' According to PTEN Pre-processing, the finding for PS3 is: 'The PTEN N69Ifs*30 variant is a truncating mutation that results in the loss of PTEN phosphatase function ... Functional studies have shown that this truncation is oncogenic.' The evidence for this variant shows: loss of phosphatase activity and oncogenic phenotype in functional assays. Therefore, this criterion is applied at Strong strength because robust functional data demonstrate a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Prevalence of the variant in affected individuals is significantly increased compared with controls or probands with specificity score ≥4.' The evidence for this variant shows: no case-control or proband specificity score data available. Therefore, this criterion is not applied due to lack of prevalence data.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: 'Located in a mutational hotspot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168).' The evidence for this variant shows: position at codon 69, outside defined catalytic motifs. Therefore, this criterion is not applied because the variant is not in a defined hotspot.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: 'Absent in population databases or present at <0.00001 allele frequency in gnomAD.' The evidence for this variant shows: MAF = 0% in gnomAD and other large databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant in recessive disorders.' The evidence for this variant shows: PTEN is associated with autosomal dominant disease, not applicable. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss variants.' The evidence for this variant shows: it is a frameshift rather than an in-frame event. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: 'Assumed de novo without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo or parental data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation and where missense is common mechanism.' The evidence for this variant shows: it is a frameshift, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect.' The evidence for this variant shows: computational tools (SpliceAI) indicate minimal splicing impact but variant is frameshift; overall in silico evidence is not needed for LOF. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: 'Patient’s phenotype is highly specific for a disease with single genetic etiology.' The evidence for this variant shows: no clinical phenotype data available. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source recently reports variant as pathogenic, but evidence is not available to perform independent evaluation.' The evidence for this variant shows: ClinVar lists this variant as Pathogenic by one clinical laboratory. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'gnomAD Filtering allele frequency >0.00056.' The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: 'Allele frequency 0.000043–0.00056 in gnomAD.' The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Observed in homozygous state in healthy PHTS-unaffected individual.' The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect.' The evidence for this variant shows: functional data demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected members of 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: 'Missense variant in gene where only truncating variants cause disease.' The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic PTEN variant or in cis multiple times.' The evidence for this variant shows: no phase data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame indels in a repetitive region without functional impact.' The evidence for this variant shows: frameshift not in a repeat region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: 'Computational evidence suggests no impact.' The evidence for this variant shows: it is a LOF frameshift with clear impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in case with alternate molecular basis for disease.' The evidence for this variant shows: no alternate diagnosis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: '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: 'Synonymous or intronic variant with no impact on splicing.' The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.