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 A333Pfs*11 variant is a truncating mutation in the tumor suppressor gene PTEN. Functional evidence indicates that truncating mutations in PTEN result in the loss of phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Experimental studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genomic fragility due to impaired chromosomal centromere association. This functional evidence supports a damaging effect of the PTEN A333Pfs*11 variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -148 bp |
| Donor Loss (DL) | 0.01 | -171 bp |
| Acceptor Gain (AG) | 0.0 | -191 bp |
| Donor Gain (DG) | 0.0 | 278 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." The evidence for this variant shows a frameshift deletion c.996del leading to a premature stop (A333Pfs*11) in a gene where loss of function is a known mechanism. Therefore, this criterion is applied at Very Strong strength because the variant clearly results in loss of function guided by 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 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 shows this variant 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 Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." There are no reported de novo observations for this variant. Therefore, this criterion is not applied.
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 is: "The PTEN A333Pfs*11 variant is a truncating mutation in the tumor suppressor gene PTEN. Functional evidence indicates that truncating mutations in PTEN result in the loss of phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Experimental studies have shown that expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genomic fragility due to impaired chromosomal centromere association. This functional evidence supports a damaging effect of the PTEN A333Pfs*11 variant." The evidence directly demonstrates damaging functional impact. Therefore, this criterion is applied at Strong strength.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs controls." There are no case-control prevalence data or specificity score reported. 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, defined to include residues in catalytic motifs: 90-94, 123-130, 166-168." This variant occurs at codon 333 outside those 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 (0.001%) allele frequency in gnomAD or another large sequenced population." The variant is absent from gnomAD and other control 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 disorder." PTEN-related conditions are autosomal dominant and no trans observations are reported. 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 deletions/insertions in a non-repeat region or stop-loss variants." This variant is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." This is not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations without confirmation of paternity/maternity." No de novo data exist. 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." No 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 a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease." This is a loss-of-function frameshift variant. 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 on the gene or gene product." A frameshift leading to truncation is already captured by PVS1; computational predictions are not required. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Patient’s phenotype is highly specific for a disease with a single genetic etiology." No phenotype 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 classifies variant as pathogenic or likely pathogenic without available evidence." No such classification exists. 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 (0.056%)." The variant is absent. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056 (0.0043%-0.056%)." The variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual." No such observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." Functional studies show 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 affected members of two or more families." 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 for which truncating variants are known mechanism of disease." 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 a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis." No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule for BP3 is: "Supporting In-frame insertions or deletions in a repetitive region without a known function." This is a frameshift variant. 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 on gene or gene product." Computational predictions are irrelevant for a clear loss-of-function variant. 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." No alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Reputable source classifies variant as benign or likely benign without available evidence." No such 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 for which splicing predictions predict no impact." This is a frameshift variant. Therefore, this criterion is not applied.