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, frameshift, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where loss-of-function is a known mechanism of disease.' The evidence for this variant shows: NM_000314.8:c.256G>C is a missense change (A86P) and does not create a null allele. 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.' The evidence for this variant shows: there is no known pathogenic variant resulting in A86P in PTEN. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.' The evidence for this variant shows: de novo status has not been established or documented. Therefore, this criterion is not applied.
PS3 (Moderate)
According to PTEN Pre-processing, the finding for PS3 is: 'Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350; score for variant = -2.1890 < threshold -1.11.' The evidence for this variant shows: a high-confidence functional score of -2.1890, which is below the -1.11 threshold. Therefore, this criterion is applied at Moderate strength because the functional assay indicates a damaging effect on protein activity.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Probands with specificity score ≥16 (Very Strong), 4–15.5 (Strong), 2–3.5 (Moderate), or 1–1.5 (Supporting).' The evidence for this variant shows: no reported probands or case counts. 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, 166-168).' The evidence for this variant shows: position 86 is outside these 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.' The evidence for this variant shows: not found in gnomAD or other large population datasets. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant.' The evidence for this variant shows: PTEN is autosomal dominant, and no phase data or second allele is reported. 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 insertions/deletions in a non-repeat region or stop-loss variants.' The evidence for this variant shows: it is a missense change with no protein length alteration. 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 pathogenic missense change has been observed, with BLOSUM62 score equal or less than the known variant.' The evidence for this variant shows: no other pathogenic missense at residue A86 is reported. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity.' The evidence for this variant shows: no de novo data are provided. 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 (Supporting: 3–4 meioses).' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation and missense is a common mechanism of disease.' The evidence for this variant shows: no quantitative data on benign missense variation rate. 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 (missense: REVEL > 0.7).' The evidence for this variant shows: no REVEL score provided and in silico predictions are mixed. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: 'Phenotype or family history highly specific for a disease with single genetic etiology.' The evidence for this variant shows: no detailed phenotype or family history provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports the variant as pathogenic.' The evidence for this variant shows: not found in ClinVar or other databases as pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone: gnomAD Filtering allele frequency >0.00056.' The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
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: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed in the homozygous state in a healthy individual.' The evidence for this variant shows: no homozygous 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.' The evidence for this variant shows: no functional studies demonstrating no impact. 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 both missense and loss-of-function. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant.' The evidence for this variant shows: no evidence of phase with other variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region.' The evidence for this variant shows: it is a missense single nucleotide change. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant shows: SpliceAI predicts no splicing impact (score 0.01) and some predictors indicate benign impact. Therefore, this criterion is applied at Supporting strength because computational data lean toward no functional 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 diagnosis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports the variant as benign.' The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Synonymous or intronic variant with no predicted splicing impact.' The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.