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 Y174Cfs*5 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 such truncating mutations are oncogenic, increasing genome fragility and disrupting chromosomal centromere association.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -26 bp |
| Donor Loss (DL) | 0.0 | 115 bp |
| Acceptor Gain (AG) | 0.0 | -9 bp |
| Donor Gain (DG) | 0.0 | 119 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: a frameshift (Y174Cfs*5) predicted to result in loss of function in PTEN, a gene where LOF is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because this is a null variant meeting the PTEN-specific PVS1 decision tree.
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 previously established PTEN pathogenic variant with the same amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 (Strong) is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: de novo status not assessed. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 (Strong) is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: studies demonstrate that Y174Cfs*5 abolishes PTEN phosphatase activity, dysregulates PI3K/AKT signaling, and is oncogenic. Therefore, this criterion is applied at Strong strength because robust functional data support a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 (Strong) is: "Prevalence of the variant in affected individuals is significantly increased compared with controls or specificity score 4–15.5." The evidence for this variant shows: no case–control or proband data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 (Moderate) is: "Located in a mutational hot spot and/or critical and well-established functional domain including residues 90–94, 123–130, 166–168." The evidence for this variant shows: position Y174 is outside the defined catalytic motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Absent in population Databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows: MAF = 0% in gnomAD. 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: no data on allelic configuration. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 (Moderate) is: "Protein length changes due to in-frame insertions/deletions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a frameshift, not an in-frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 (Moderate) is: "Missense change at a residue where a different missense change is pathogenic." 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 (Strong) is: "Two probands with presumed de novo occurrence without confirmation." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 (Supporting) is: "Co-segregation with disease in multiple affected family members (3–4 meioses)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines, the rule for PP2 (Supporting) is: "Missense variant in a gene with low benign missense rate where missense is a common mechanism." 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 (Supporting) is: "Multiple lines of computational evidence support deleterious effect (REVEL>0.7 for missense)." The evidence for this variant shows: insufficient in silico data for splicing or missense. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Phenotype highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no patient phenotype provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
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: MAF = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 (Strong) is: "Allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 (Strong) is: "Observed in homozygous state in healthy individual." 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 (Strong) is: "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 (Strong) is: "Lack of segregation in affected members of two 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 truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 (Supporting) is: "Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no data on allelic phase. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame insertion/deletion in a repetitive region without functional impact." 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 (Supporting) is: "Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: no computational support for benign effect. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 (Supporting) is: "Variant found in case with alternate molecular basis for disease." The evidence for this variant shows: no such alternate basis. 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 without evidence." The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 (Supporting) is: "Synonymous or intronic variant with no splicing impact predicted." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.