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"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN G251D variant is located in the C2 tensin-type domain and is associated with decreased PTEN protein levels and increased phosphorylation of AKT and S6, indicating an inactivating effect. However, the variant has not been biochemically characterized to directly assess its impact on PTEN protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -261 bp |
| Donor Loss (DL) | 0.0 | -138 bp |
| Acceptor Gain (AG) | 0.01 | -63 bp |
| Donor Gain (DG) | 0.0 | -8 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines the rule for PVS1 is: "Use PTEN PVS1 decision tree." The evidence for this variant shows it is a missense change (G251D), 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, where in silico models predict impact equal to or greater than the known pathogenic variant." The evidence for this variant shows no previously established pathogenic change at glycine 251. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines the rules for PS2 are: "Very Strong: Two proven OR four assumed OR one proven + two assumed de novo observations..." and "Strong: De novo (both maternity and paternity confirmed) observation..." The evidence for this variant shows no de novo data. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to PTEN Pre-processing the finding for PS3 is: "High confidence not TRUE ('FALSE'), PS3 rule not applied." The evidence for this variant shows functional studies did not meet the threshold per PTEN-specific pre-processing. Therefore, this criterion is not applied.
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 series or prevalence data. Therefore, this criterion is not applied.
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. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168." The evidence for this variant shows glycine 251 is outside those defined motifs. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines the rule for PM2 is: "Supporting: Absent in population databases present at <0.00001 allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows it is absent from gnomAD (MAF = 0%). 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-associated disease is dominant and no trans observation. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines the rule for PM4 is: "Moderate: Protein length changes due to in-frame deletions/insertions..." The evidence for this variant shows a missense change, not an in-frame indel. Therefore, this criterion is not applied.
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 or likely pathogenic has been seen before." The evidence for this variant shows no other pathogenic missense reported at glycine 251. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines the rules for PM6 are: "Very Strong: Two proven OR four assumed OR one proven + two assumed de novo observations..." and "Strong: Two probands with presumed de novo occurrence..." The evidence for this variant shows no de novo or family data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines the rule for PP1 is: "Supporting: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines the rule for PP2 is: "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." The evidence for PTEN shows both benign and pathogenic missense are observed, so this criterion is not applied.
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. Missense variants: REVEL score > 0.7." The evidence for this variant shows a REVEL score of 0.95. Therefore, this criterion is applied at Supporting strength because computational data strongly support deleterious effect.
PP4 (Not Applied)
According to standard ACMG guidelines the rule for PP4 is: "Supporting: Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows no detailed clinical phenotype. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines the rule for PP5 is: "Supporting: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows ClinVar lists it as Likely Pathogenic by one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable source reports pathogenicity.
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 = 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 = 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 or PHTS-unaffected 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: "Strong: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function." The evidence for this variant shows functional studies indicate reduced PTEN activity. Therefore, this criterion is not applied.
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 segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines the rule for BP1 is: "Supporting: Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for PTEN shows missense is a known mechanism. Therefore, this criterion is not applied.
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 such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines the rule for BP3 is: "Supporting: In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows a missense change, not an in-frame indel. Therefore, this criterion is not applied.
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. Missense variants: REVEL scores < 0.5." The evidence for this variant shows REVEL = 0.95. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to standard ACMG 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 alternate diagnosis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines the rule for BP6 is: "Supporting: Reputable source reports variant as benign without available evidence." The evidence for this variant shows only pathogenic classifications. Therefore, this criterion is not applied.
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 impact on splicing." The evidence for this variant shows a missense change. Therefore, this criterion is not applied.