Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| 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 |
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
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) | 0.0 | -2 bp |
| Donor Loss (DL) | 0.0 | 236 bp |
| Acceptor Gain (AG) | 0.01 | -20 bp |
| Donor Gain (DG) | 0.0 | 4 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease." The evidence for this variant shows: it is a missense change (A86P), not a null variant. Therefore, this criterion is not applied.
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 OR different variant at same nucleotide position as a pathogenic splicing variant..." The evidence for this variant shows: no previously established pathogenic variant results in A86P. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "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 status has been documented. Therefore, this criterion is not applied.
PS3 (Moderate)
According to PTEN Pre-processing guidelines, the finding for PS3_Moderate is: "Phosphatase activity ≤ -1.11 per Mighell et al. 2018, score -2.1890 < -1.11." The evidence for this variant shows: functional score of -2.1890 meets the threshold. Therefore, this criterion is applied at Moderate strength because the functional assay demonstrates a damaging effect below the PTEN-specific threshold.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Probands with specificity score 4-15.5 OR prevalence significantly increased compared with controls." The evidence for this variant shows: no case-level proband specificity data or prevalence data. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94, 123-130)." The evidence for this variant shows: residue A86 is outside the defined catalytic motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Absent in population Databases present at <0.00001 allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows: MAF = 0% in gnomAD and other databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "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." The evidence for this variant shows: no trans or cis observations with PTEN pathogenic variants. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a single amino acid substitution. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Missense change at a residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before." The evidence for this variant shows: no other pathogenic missense at residue A86. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Assumed de novo without confirmation of paternity/maternity in a patient with the disease." The evidence for this variant shows: no de novo assumption. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members (3-4 meioses for supporting)." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: insufficient data on benign missense rate in PTEN to apply PP2. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect; for missense, REVEL score > 0.7." The evidence for this variant shows: mixed in silico predictions and no REVEL score >0.7. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: not found in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "gnomAD Filtering allele frequency >0.00056." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "gnomAD Filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Observed in the homozygous state in a healthy or PHTS-unaffected individual." The evidence for this variant shows: no homozygous healthy observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect or phosphatase activity >0 per Mighell et al. 2018." The evidence for this variant shows: functional score -2.1890 indicates damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: PTEN disease mechanism includes missense and LOF; cannot apply BP1. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis with different pathogenic variants." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule for BP3 is: "In-frame insertions/deletions in a repetitive region without a known function." The evidence for this variant shows: single amino acid substitution. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product; for missense, REVEL scores < 0.5." The evidence for this variant shows: mixed in silico results with SpliceAI score 0.01 indicating no splicing impact and overall conflicting predictions. Therefore, this criterion is applied at Supporting strength because computational evidence does not support a deleterious effect.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant at or beyond +7/-21 with no splicing impact." The evidence for this variant shows: it is missense. Therefore, this criterion is not applied.