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 D324Efs*17 variant is a truncating mutation that results in the loss of PTEN phosphatase function. Functional studies have demonstrated that such truncating mutations lead to an inability to negatively regulate PI3K/AKT pathway activity and increase genome fragility due to impaired chromosomal centromere association. These effects support a damaging and likely oncogenic role for this variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -125 bp |
| Donor Loss (DL) | 0.0 | 56 bp |
| Acceptor Gain (AG) | 0.0 | 124 bp |
| Donor Gain (DG) | 0.01 | -148 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 truncating mutation (D324Efs*17) in PTEN, where loss-of-function is a known mechanism of disease, and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant meets the PTEN-specific PVS1 decision tree for null variants.
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, where in silico models predict impact equal to or greater than the known pathogenic variant. Modification Type: Disease-specific." The evidence for this variant shows no prior report of the same amino acid change at this residue. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "**Strong Strength**: Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. Modification Type: None." There is no de novo data available for this variant. Therefore, this criterion is not applied.
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 is: "The PTEN D324Efs*17 variant is a truncating mutation that results in the loss of PTEN phosphatase function. Functional studies demonstrate inability to negatively regulate PI3K/AKT pathway and increased genome fragility." 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. RNA, mini-gene, or other assay shows impact on splicing. Modification Type: Disease-specific." The evidence for this variant shows well-established functional studies demonstrating loss of function. Therefore, this criterion is applied at Strong strength.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "**Strong Strength**: Strong Probands with specificity score 4-15.5 OR the prevalence of the variant in affected individuals is significantly increased compared with controls. Modification Type: Strength." There are no case series or prevalence data 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. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3). Modification Type: Disease-specific." The D324Efs*17 frameshift lies outside these 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 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%). Modification Type: Disease-specific." The evidence for this variant shows it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "Moderate Strength: Detected in trans with a pathogenic variant for a recessive disorder." PTEN-related disorders are autosomal dominant and no compound heterozygosity data are available. 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. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif, and variants causing protein extension. Modification Type: Disease-specific." This variant is a frameshift leading to truncation, not an in-frame change. 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 or likely pathogenic has been seen before. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant. Modification Type: Disease-specific." This 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: "**Strong Strength**: Strong Two probands with presumed de novo occurrence (maternity/paternity not confirmed) with the disease and no family history; may also be used for a proband with presumed de novo occurrence for an individual with a highly specific phenotype. Modification Type: Strength." No de novo or proband 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 multiple affected family members, with ≥7 meioses observed across at least two families. Modification Type: Strength." 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 that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." This variant is a frameshift, not a missense change. 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 on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL score > 0.7. Modification Type: Disease-specific." While splicing calculators show minimal impact (SpliceAI max = 0.01), the variant is a frameshift causing LoF. Computational evidence for splicing is inconsistent with LoF mechanism assessment. 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 specific phenotypic 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 Strength: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." This variant is not found in ClinVar or other reputable 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 (0.056%)." This variant is absent from gnomAD. 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 (0.0043%) up to 0.00056 (0.056%). Modification Type: Disease-specific." This variant is absent from gnomAD. 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. One observation if homozygous status confirmed, two if not confirmed. To be applied at supporting evidence level if BS1 is also applied. Modification Type: Disease-specific." No homozygous observations in unaffected individuals are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "**Strong Strength**: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact. Modification Type: Disease-specific." Functional studies show 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 two or more families. Modification Type: Disease-specific." No segregation data indicating lack of segregation are 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 a gene for which primarily truncating variants are known to cause disease." This is a truncating variant, not a 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 or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants. Modification Type: Disease-specific." No such trans or cis observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame deletions/insertions in a repetitive region without a known function." 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 on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL scores < 0.5. Modification Type: Disease-specific." Although splicing algorithms predict minimal impact, the frameshift causes loss of function. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease." No alternate molecular etiology 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 recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." No benign report exists. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact... Modification Type: Disease-specific." This variant is neither synonymous nor intronic. Therefore, this criterion is not applied.