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) | 0.91 | -143 bp |
| Donor Loss (DL) | 0.99 | -2 bp |
| Acceptor Gain (AG) | 0.0 | 0 bp |
| Donor Gain (DG) | 0.0 | 27 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: an insertion at the canonical +2 splice donor site (c.634+2_634+3insGC) predicted to abolish normal splicing and cause loss of function in PTEN, a known LoF disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant disrupts a canonical splice site in a gene where loss of function is established as pathogenic.
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 for this variant shows: no previously reported pathogenic variant at this splice junction resulting in the same effect. Therefore, this criterion is not applied because there is no known pathogenic variant at the same site.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." The evidence for this variant shows: no de novo inheritance data available. Therefore, this criterion is not applied because de novo status has not been demonstrated.
PS3 (Not Applied)
According to PTEN Pre-processing, the finding for PS3 is: "The variant has not been functionally characterized." The evidence for this variant shows: no well-established in vitro or in vivo functional assays (e.g., RNA or mini-gene) demonstrating an impact on splicing or protein function. Therefore, this criterion is not applied because functional data are lacking.
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." The evidence for this variant shows: no case data or proband specificity score available. Therefore, this criterion is not applied because there is no evidence of increased prevalence in affected individuals.
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 (e.g., residues 90-94, 123-130, 166-168)." The evidence for this variant shows: the change is intronic at +2/+3, outside defined catalytic motifs. Therefore, this criterion is not applied because the variant is not within a documented functional hotspot.
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." The evidence for this variant shows: not found in gnomAD or other control databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population cohorts.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Moderate For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN disease is autosomal dominant and there is no trans observation. Therefore, this criterion is not applied because PM3 is not relevant for autosomal dominant inheritance.
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." The evidence for this variant shows: an intronic insertion that does not change protein length directly. Therefore, this criterion is not applied because there is no in-frame protein change.
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." The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied because PM5 applies only to missense changes.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Moderate Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no inheritance information. Therefore, this criterion is not applied because de novo status is not assumed or reported.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied because segregation information is unavailable.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Missense variant in a gene with low rate of benign missense variation and where missense variants are a common disease mechanism." The evidence for this variant shows: it is an intronic splice variant, not missense. Therefore, this criterion is not applied because PP2 applies only to missense variants.
PP3 (Supporting)
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. Splicing variants: Concordance of SpliceAI and VarSeak." The evidence for this variant shows: SpliceAI donor loss score of 0.99 and acceptor loss score of 0.91 predicting high impact on splicing. Therefore, this criterion is applied at Supporting strength because in silico models concordantly predict disruption of normal splicing.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting Phenotype specific for disease with single genetic etiology." The evidence for this variant shows: no patient phenotype data provided. Therefore, this criterion is not applied because phenotype specificity cannot be assessed.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied because no external pathogenic assertion exists.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied because allele frequency is not above the BA1 threshold.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong gnomAD filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied because allele frequency does not meet BS1.
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." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied because there are no healthy homozygote data.
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." The evidence for this variant shows: no functional studies demonstrating lack of effect. Therefore, this criterion is not applied because no assay data support absence of damage.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members of two or more families." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied because segregation evidence is not available.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Missense variant in a gene for which truncating variants are known mechanism." The evidence for this variant shows: it is a splice variant, not missense. Therefore, this criterion is not applied because BP1 applies only to missense variants.
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." The evidence for this variant shows: no cis/trans phase data. Therefore, this criterion is not applied because there is no information on co-occurrence.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: an intronic insertion not in a repeat region. Therefore, this criterion is not applied because BP3 does not apply.
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." The evidence for this variant shows: computational tools predict high impact on splicing. Therefore, this criterion is not applied because in silico evidence indicates deleterious effect.
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." The evidence for this variant shows: no case reports with alternate molecular diagnoses. Therefore, this criterion is not applied because no such case data exist.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Reputable source reports variant as benign without evidence." The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied because no benign assertions are available.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact." The evidence for this variant shows: insertion at +2/+3 predicted to disrupt splicing. Therefore, this criterion is not applied because the variant affects the canonical splice site.