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 Y27Vfs*17 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 demonstrated that such truncating mutations are oncogenic, increasing genomic 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) | 0.08 | -93 bp |
| Donor Loss (DL) | 0.12 | 1 bp |
| Acceptor Gain (AG) | 0.04 | -297 bp |
| Donor Gain (DG) | 0.12 | 90 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. Null Variant in a gene where LOF is a known mechanism of disease." The evidence for this variant shows: NM_000314.8:c.78_79insG (Y27Vfs*17) is a frameshift leading to a premature stop codon early in the transcript, not in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a null variant in PTEN where loss of function is a known disease mechanism and not in the last exon.
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: Y27Vfs*17 is a frameshift, not the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong/Strong: De novo observations in a patient with the disease and no family history (strength depends on confirmation)." The evidence for this variant shows: No de novo data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong: 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 Y27Vfs*17 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to oncogenic effects demonstrated in functional assays." The evidence for this variant shows: Functional studies demonstrate complete loss of PTEN phosphatase activity and oncogenic impact. Therefore, this criterion is applied at Strong strength because well-established assays show a damaging effect on PTEN function.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Very Strong/Strong/Moderate/Supporting: Increased prevalence in affected individuals or proband specificity score thresholds." The evidence for this variant shows: No case series 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 hotspot or critical functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: Y27Vfs*17 lies outside known critical PTEN domains. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent in population databases at <0.00001 allele frequency in gnomAD or another large database." The evidence for this variant shows: Not found in gnomAD or other population databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large control datasets.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Moderate: Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: No evidence of a recessive genotype or trans observations. 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 indels or stop-loss variants." The evidence for this variant shows: This is a frameshift leading to truncation, not an in-frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate: Novel missense at a residue where another missense change is pathogenic." The evidence for this variant shows: Y27Vfs*17 is a frameshift, not a missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Very Strong/Strong/Moderate: Assumed de novo observations without full confirmation." The evidence for this variant shows: No de novo information available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong: Co-segregation with disease in multiple affected family members." The evidence for this variant shows: No family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense in a gene with low benign missense rate and where missense is common." The evidence for this variant shows: It is a frameshift. 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 (REVEL>0.7 for missense; SpliceAI/VarSeak for splicing)." The evidence for this variant shows: SpliceAI max score 0.12 (below threshold) and no high REVEL. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Supporting: Phenotype or family history highly specific for a single gene disorder." The evidence for this variant shows: No 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 without available evidence." The evidence for this variant shows: No such reports. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Allele frequency >0.00056 in gnomAD." The evidence for this variant shows: Not present in gnomAD. 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 in gnomAD." The evidence for this variant shows: Not present in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong/Supporting: Observed in homozygous state in healthy individuals." The evidence for this variant shows: No such observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established functional studies show no damaging effect." The evidence for this variant shows: Functional studies show damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong/Supporting: 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 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 a dominant disorder." The evidence for this variant shows: No such data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame indels in repetitive regions without known function." The evidence for this variant shows: Frameshift outside repeat region. 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." The evidence for this variant shows: Computational tools are inconclusive but functional data show damaging effect. 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 VCEP guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign without evidence." The evidence for this variant shows: No such 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 predicted splicing impact." The evidence for this variant shows: It is a frameshift. Therefore, this criterion is not applied.