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 Y46Rfs*7 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 demonstrated that such truncating mutations in PTEN are oncogenic, as they increase genomic fragility and disrupt PTEN's association with chromosomal centromeres. This evidence supports a damaging effect of the variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.04 | -58 bp |
| Donor Loss (DL) | 0.0 | 33 bp |
| Acceptor Gain (AG) | 0.04 | -12 bp |
| Donor Gain (DG) | 0.0 | 28 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: it is an early frameshift (Y46Rfs*7) predicted to result in loss of function in a gene where LOF is a known disease mechanism and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because the PTEN-specific decision tree supports PVS1 for truncating variants outside the last exon.
PS1 (Not Applied)
According to VCEP guidelines the rule for PS1 is: "Strong Strength: 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: it is a frameshift, not a missense change at a previously characterized position. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines the rule for PS2 is: "Very Strong Strength: 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 data are available. Therefore, this criterion is not applied.
PS3 (Strong)
According to PTEN Pre-processing the finding for PS3 is: "The PTEN Y46Rfs*7 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 demonstrated that such truncating mutations in PTEN are oncogenic..." According to VCEP guidelines the rule for PS3 is: "Strong Strength: Strong 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: functional assays demonstrate loss of phosphatase activity and oncogenic behavior. Therefore, this criterion is applied at Strong strength.
PS4 (Not Applied)
According to VCEP guidelines the rule for PS4 is: "Very Strong Strength: Very Strong Probands with specificity score ≥16..." The evidence for this variant shows: no case or prevalence data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines the rule for PM1 is: "Moderate Strength: 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: it affects codon 46, outside of defined critical domains. 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 (0.001%) allele frequency in gnomAD..." The evidence for this variant shows: it is absent from gnomAD and other large population databases. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive gene/disorder." The evidence for this variant shows: PTEN-associated disease is autosomal dominant and no in trans data exist. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines the rule for PM4 is: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a frameshift, not an in-frame change or stop-loss. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines the rule for PM5 is: "Moderate Strength: Moderate 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 substitution. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines the rule for PM6 is: "Very Strong Strength: Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations..." The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines the rule for PP1 is: "Strong Strength: Strong Co-segregation with disease in ≥7 meioses across ≥2 families..." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to VCEP guidelines the rule for PP2 is: "Supporting Strength: Supporting Missense variant in a gene with low 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: "Supporting Strength: Supporting Multiple lines of computational evidence support deleterious effect (REVEL >0.7 or splice algorithms)." The evidence for this variant shows: no strong computational predictions of deleteriousness beyond LOF. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines the rule for PP4 is: "Supporting Phenotype or family history 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 (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: no reputable external classification is available. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines the rule for BA1 is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." 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 Strength: Strong gnomAD Filtering allele frequency from 0.000043 to 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 Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual..." The evidence for this variant shows: no homozygous observations in unaffected individuals. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines the rule for BS3 is: "Strong Strength: Strong Well-established 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 Strength: Strong Lack of segregation in affected members of ≥2 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 only truncations cause disease." The evidence for this variant shows: it is a truncating variant and truncations are disease-causing. 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 PTEN variant or ≥3 observations in cis..." The evidence for this variant shows: no such observations. 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 without known function." The evidence for this variant shows: it is a frameshift, 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..." The evidence for this variant shows: it is clearly LOF by frameshift. 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 such benign classification exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines the rule for BP7 is: "Supporting A synonymous or intronic variant at or beyond +7/-21 with no predicted splice impact." The evidence for this variant shows: it is a frameshift, not synonymous or deep intronic. Therefore, this criterion is not applied.