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
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 1.0 | 6 bp |
| Donor Loss (DL) | 0.02 | 26 bp |
| Acceptor Gain (AG) | 0.89 | 49 bp |
| Donor Gain (DG) | 0.0 | 90 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines for PTEN PVS1: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows it is an intronic deletion at positions -5 to -2, outside the canonical +/−1,2 splice sites. Therefore, this criterion is not applied because the variant does not meet the canonical splice site requirement for PVS1.
PS1 (Not Applied)
According to VCEP guidelines for PS1: "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.". The evidence for this variant shows it is an intronic deletion with no amino acid change and no known pathogenic splice variant at the exact nucleotides. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines for PS2: "Strong Strength: Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.". There is no information on de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to PTEN Pre-processing finding for PS3: "The PTEN 802-5_802-2del variant has not been functionally characterized.". The evidence for this variant shows no in vitro or in vivo functional studies. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines for PS4: "Strong Strength: Strong Probands with specificity score 4-15.5 or prevalence significantly increased in affected versus controls.". There are no case reports or proband specificity scores for this variant. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines for PM1: "Moderate Strength: Moderate Located in a mutational hot spot and/or critical and well-established functional domain (catalytic motifs 90-94, 123-130, 166-168).". The evidence shows the variant is intronic and not within any PTEN catalytic motif. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines for PM2: "Supporting Strength: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.". The evidence for this variant shows a MAF of 0% in gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to Standard ACMG for PM3: "Detected in trans with a pathogenic variant for a recessive disorder.". PTEN-related disease is autosomal dominant and no evidence of trans occurrence is reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines for PM4: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.". The evidence shows this is an intronic deletion without a predicted in-frame effect on protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines for PM5: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.". This variant is intronic and not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines for PM6: "Moderate Strength: Moderate Assumed de novo, but without confirmation of paternity and maternity.". There is no de novo evidence available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines for PP1: "Supporting Strength: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.". There are no segregation data for this variant. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to Standard ACMG for PP2: "Supporting 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 is an intronic deletion, not a missense variant. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines for PP3: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak.". The evidence for this variant shows a SpliceAI acceptor loss score of 1.0, indicating high likelihood of splicing disruption. Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to Standard ACMG for PP4: "Supporting Patient’s phenotype or family history highly specific for a disease with a single genetic etiology.". No phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to Standard ACMG for PP5: "Supporting Reputable source reports variant as pathogenic without available evidence.". No such reports exist for this variant. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines for BA1: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%).". The evidence shows an allele frequency of 0% in gnomAD, below threshold. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines for BS1: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056.". The allele frequency is 0%, outside the BS1 range. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines for BS2: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual.". No homozygous observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines for BS3: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.". There are no functional studies demonstrating lack of effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines for BS4: "Strong Strength: Strong Lack of segregation in affected members of two or more families.". No segregation data are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to Standard ACMG for BP1: "Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease.". This is an intronic deletion, not a missense variant. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines for BP2: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant.". There is no evidence of this variant in trans with another PTEN pathogenic variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to Standard ACMG for BP3: "Supporting In-frame deletions/insertions in a repetitive region without a known function.". This deletion is intronic and not in a repetitive region. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines for BP4: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak.". Computational evidence indicates a high splicing impact. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines for BP5: "Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease.". No such case data are available. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to Standard ACMG for BP6: "Supporting Reputable source reports variant as benign without available evidence.". No such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines for BP7: "Supporting Strength: Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.". This variant is at positions -5 to -2, within the splice region and predicted to impact splicing. Therefore, this criterion is not applied.