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 Y46H variant results in reduced phosphatase activity in a yeast assay, indicating a loss of PTEN protein function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 94 bp |
| Donor Loss (DL) | 0.0 | 131 bp |
| Acceptor Gain (AG) | 0.05 | -63 bp |
| Donor Gain (DG) | 0.05 | 28 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, PVS1 applies to null variants following the PTEN PVS1 decision tree; this variant is a missense change. The evidence for this variant shows it is not predicted to result in loss of the reading frame. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, PS1 (Strong) requires the same amino acid change as a previously established pathogenic variant. The evidence for this variant shows a novel Y46H change with no identical pathogenic amino acid change reported. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, PS2 (Strong) requires confirmed de novo occurrence in a patient. No de novo information is available for this variant. Therefore, this criterion is not applied.
PS3 (Moderate)
According to PTEN Pre-processing, the rule for PS3_Moderate is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Phosphatase activity ≤ -1.11 per Mighell et al. 2018". The evidence for this variant shows a phosphatase activity score of -2.7199, which is below -1.11. Therefore, this criterion is applied at Moderate strength.
PS4 (Not Applied)
According to VCEP guidelines, PS4 requires an increased prevalence in affected individuals or probands with specificity score ≥4. No case or specificity score data are available for this variant. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 (Moderate) applies if the variant is located in a PTEN catalytic motif (residues 90–94, 123–130, 166–168). The evidence for this variant shows position 46, outside defined hotspots. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 (Supporting) is: "Absent in population databases present at <0.00001 allele frequency in gnomAD." The evidence for this variant shows 0% frequency in gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, PM3 applies to variants detected in trans with a pathogenic variant in a recessive disorder. PTEN-associated disease is autosomal dominant, and no trans observations are reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, PM4 (Moderate) applies to in-frame indels or stop-loss variants. This variant is a missense change. Therefore, this criterion is not applied.
PM5 (Moderate)
According to VCEP guidelines, PM5 (Moderate) is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before, with equal or more deleterious BLOSUM62 score." The evidence for this variant shows a previously reported pathogenic missense at residue 46 (e.g., Y46C in ClinVar) and the BLOSUM62 score for the histidine substitution is equal or more deleterious. Therefore, this criterion is applied at Moderate strength.
PM6 (Not Applied)
According to standard ACMG guidelines, PM6 (Strong) applies to assumed de novo occurrences without confirmation. No de novo assumptions are reported. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 requires co-segregation in multiple affected family members. No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, PP2 (Supporting) requires a missense variant in a gene with a low rate of benign missense variation. Insufficient data on benign missense rate in PTEN are available here. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, PP3 (Supporting) is: "Multiple lines of computational evidence support a deleterious effect; missense variants: REVEL score > 0.7." The evidence for this variant shows a REVEL score of 0.96. Therefore, this criterion is applied at Supporting strength.
PP4 (Not Applied)
According to standard ACMG guidelines, PP4 requires a highly specific phenotype. No clinical phenotype details are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, PP5 (Supporting) requires a reputable source reporting the variant as pathogenic. ClinVar lists this variant as Likely Pathogenic, not Pathogenic, and no additional evidence is available. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 (Stand Alone) requires allele frequency >0.056% in gnomAD. The evidence shows 0% frequency. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 (Strong) requires allele frequency 0.0043%–0.056% in gnomAD. The evidence shows 0% frequency. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 applies if observed homozygous in healthy individuals. No such observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 requires functional studies showing no damaging effect. Functional data show reduced activity. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 requires lack of segregation in multiple families. No segregation data exist. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, BP1 (Supporting) applies to missense variants in genes where only truncating variants cause disease. PTEN disease mechanism includes missense variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, BP2 requires observations in trans or multiple cis observations with other pathogenic variants. No such observations are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 requires computational evidence suggesting no impact (REVEL <0.5). The evidence shows REVEL 0.96. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, BP5 requires an alternate molecular basis in a case. No such alternate basis is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, BP6 (Supporting) requires reputable source reporting benign. No benign reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This is a missense variant. Therefore, this criterion is not applied.