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 E307Rfs*5 variant is a truncating mutation that results in the production of C-terminally truncated PTEN proteins. Functional studies have shown that such truncating mutations lead to a loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Additionally, expression of PTEN truncation mutations in mouse embryonic fibroblasts has demonstrated oncogenic properties and increased genomic fragility due to the inability of truncated PTEN to associate with chromosomal centromeres. These findings support a damaging effect of the PTEN E307Rfs*5 variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -72 bp |
| Donor Loss (DL) | 0.01 | -95 bp |
| Acceptor Gain (AG) | 0.0 | 177 bp |
| Donor Gain (DG) | 0.0 | 354 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. Modification Type: Disease-specific." The evidence for this variant shows a frameshift (NM_000314.8:c.918dup; E307Rfs*5) resulting in a truncated PTEN protein not in the last exon, consistent with loss-of-function. Therefore, this criterion is applied at Very Strong strength because a null variant in PTEN is a known mechanism of disease per the decision tree.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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 a frameshift, not the same amino acid change as any known pathogenic missense or splicing variant. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history." No de novo data are available for this case. Therefore, this criterion is not applied.
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." The evidence shows that E307Rfs*5 truncating mutations abolish PTEN phosphatase function, dysregulate PI3K/AKT signaling, and confer oncogenic properties in cellular assays and mouse models. Therefore, this criterion is applied at Strong strength because functional studies demonstrate a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Very Strong Strength: Probands with specificity score ≥16 OR Strong Strength: specificity score 4–15.5 or significant increase in prevalence in cases vs controls." No case count 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: Located in a mutational hot spot and/or critical and well-established functional domain (residues 90–94, 123–130, 166–168)." The variant at residue 307 lies outside these domains. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Absent in population databases present at <0.00001 allele frequency in gnomAD or another large sequenced population." The evidence shows this variant is not observed in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it 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." No inheritance or trans data are available for this variant in PTEN. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels or stop-loss variants." This variant is a frameshift leading to premature termination, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." This variant 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: "Very Strong/Strong/Moderate Strength: Assumed de novo observations without confirmation." No de novo or family history data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong Strength: 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 Strength: Missense variant in a gene with low rate of benign missense variation where missense is common disease mechanism." This is a loss-of-function variant, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect (REVEL>0.7 or splicing concordance)." In silico predictions (SpliceAI max score 0.01) do not support a deleterious effect on splicing or protein function. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No detailed phenotype or family history specific to PTEN-related syndrome is provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source reports variant as pathogenic without accessible evidence." This variant is not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD Filtering allele frequency >0.00056." This variant’s frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: allele frequency from 0.000043 up to 0.00056." This variant’s frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong/Supporting Strength: Homozygous observations in healthy individuals." No homozygosity data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong/Supporting Strength: Well-established functional studies show no damaging effect." Functional studies for this variant demonstrate damaging effects. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong/Supporting Strength: Lack of segregation in affected members." No segregation evidence demonstrating lack of segregation is available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense variant in gene where loss-of-function is mechanism." This variant is a frameshift causing loss-of-function, not a benign missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Observed in trans with a pathogenic variant or multiple in cis." No such observations are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame indels in repetitive regions without functional impact." This variant 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 Strength: Multiple lines of computational evidence suggest no impact." SpliceAI predicts no significant splicing effect, but the variant’s frameshift nature overrides computational predictions. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Supporting Strength: 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 Strength: Reputable source reports variant as benign without available evidence." No such benign assertion exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous or intronic variant with no predicted splicing impact." This variant is a frameshift. Therefore, this criterion is not applied.