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 V54Efs*2 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 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) | 0.02 | -107 bp |
| Donor Loss (DL) | 0.0 | 221 bp |
| Acceptor Gain (AG) | 0.03 | -85 bp |
| Donor Gain (DG) | 0.02 | 6 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 it is a frameshift (c.159_160dup, V54Efs*2) causing a null allele in PTEN, a gene where loss of function is a known disease mechanism and the variant does not occur in the last exon. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific truncating variant rule.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows a novel frameshift change with no matching known pathogenic amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "De novo occurrence confirmed by paternity and maternity." There is no information on de novo status for this variant. 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 for this variant shows functional studies demonstrating loss of PTEN phosphatase activity and oncogenic effect. Therefore, this criterion is applied at Strong strength because it meets the PTEN-specific functional evidence requirement.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared with controls or probands with specificity score ≥4." There are no case-control or proband specificity data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hotspot or critical functional domain (residues 90-94, 123-130, 166-168)." The variant at residue 54 is outside these motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent in population databases (allele frequency <0.00001 in gnomAD)." The evidence for this variant shows it is not present in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to recessive disorders with trans observations. PTEN-related disease is autosomal dominant and no trans data are relevant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, PM4 applies to in-frame indels causing protein length changes. This variant is a frameshift leading to truncation. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 applies to novel missense changes at residues with known pathogenic missense variants. This is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, PM6 applies to assumed de novo occurrences without confirmation. No de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 applies to co-segregation with disease in multiple affected family members. No segregation data are provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense rate. This is a frameshift variant. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 requires multiple lines of computational evidence supporting deleterious effect. Computational analyses show minimal splicing impact and no high REVEL score. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 applies when the phenotype is highly specific for a single gene disorder. No phenotype data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 applies when reputable sources report variant as pathogenic without evidence. The variant is not in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 applies to allele frequency >0.056%. The variant frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 applies to allele frequency 0.0043–0.056%. The variant frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies to observation in homozygous state in unaffected individuals. No such data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 applies to functional studies showing no damaging effect. Functional studies for this variant show damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 applies to lack of segregation in multiple families. No segregation data are provided. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. This variant is truncating. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, BP2 applies to observations in trans with pathogenic PTEN variants. No such data are available. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is a frameshift. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." Computational analysis shows minimal predicted splicing impact (SpliceAI 0.03). Therefore, this criterion is applied at Supporting strength because computational data predict no impact.
BP5 (Not Applied)
According to standard ACMG guidelines, BP5 applies when an alternate molecular basis for disease is present. No such alternate basis is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 applies when a variant is reported benign by a reputable source without evidence. No such report exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This variant is coding and frameshifting. Therefore, this criterion is not applied.