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
The PTEN H64Lfs*35 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have shown that such truncating mutations in PTEN are oncogenic, as they increase genome fragility and disrupt PTEN's association with chromosomal centromeres. This evidence supports a damaging effect of the variant.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 491 bp |
| Donor Loss (DL) | 0.03 | 23 bp |
| Acceptor Gain (AG) | 0.01 | -25 bp |
| Donor Gain (DG) | 0.0 | 19 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, PVS1: Very Strong Use PTEN PVS1 decision tree. The rule for PVS1 is: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: NM_000314.8:c.191del is a frameshift predicted to trigger NMD in an exon that is not the last exon, and LOF is a known disease mechanism for PTEN. Therefore, this criterion is applied at Very Strong strength because the variant is a null variant and meets the PTEN PVS1 decision tree criteria.
PS1 (Not Applied)
According to VCEP guidelines, PS1 Strong: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." There is no known pathogenic variant with the same amino acid change at position H64. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to VCEP guidelines, PS2 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..." There are no de novo data available for this variant. Therefore, this criterion is not applied.
PS3 (Strong)
According to VCEP guidelines, PS3 Strong: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." According to PTEN pre-processing, functional studies of H64Lfs*35 show loss of PTEN phosphatase function leading to oncogenic activity. Therefore, this criterion is applied at Strong strength because well-established functional assays demonstrate a damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, PS4 Strong: "Probands with specificity score 4–15.5 or increased prevalence in affected versus controls." No case-level prevalence or specificity data are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to VCEP guidelines, PM1 Moderate: "Located in a mutational hot spot and/or critical functional domain (residues 90–94, 123–130, 166–168)." The variant affects residue 64, which is outside these critical domains. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, PM2 Supporting: "Absent in population databases present at <0.001% allele frequency in gnomAD or other large populations." The variant is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it is absent from population controls.
PM3 (Not Applied)
According to VCEP guidelines, PM3 is for recessive disorders: "Detected in trans with a pathogenic variant in recessive gene." PTEN-related disease is autosomal dominant. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, PM4 Moderate: "Protein length changes due to in-frame indels or stop-loss variants." This is a frameshift leading to premature termination, not an in-frame change. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, PM5 Moderate: "Different missense change at an amino acid residue where another missense has been determined pathogenic." This variant is a frameshift, not a missense. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, PM6 Very Strong/Strong: "De novo observations without full confirmation..." No de novo information is available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, PP1 Supporting: "Co-segregation with disease in multiple affected family members (3–4 meioses)." No segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to ACMG guidelines, PP2 Supporting: "Missense variant in a gene with low rate of benign missense variation and where missense variants are common mechanism." The variant is a frameshift. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, PP3 Supporting: "Multiple lines of computational evidence support a deleterious effect (SpliceAI/REVEL thresholds)." SpliceAI max score is 0.03 (below threshold) and REVEL is not applicable. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to ACMG guidelines, PP4 Supporting: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." No phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to ACMG guidelines, PP5 Supporting: "Reputable source (e.g., ClinVar) reports variant as pathogenic." This variant is not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, BA1 Stand Alone: "gnomAD filtering allele frequency >0.056%." The variant is absent in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, BS1 Strong: "gnomAD allele frequency 0.0043%–0.056%." The variant is absent. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, BS2 Strong: "Observed in the homozygous state in a healthy or PHTS-unaffected individual." No homozygous observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, BS3 Strong: "Well-established in vitro or in vivo functional studies show no damaging effect." Functional studies for this variant show damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, BS4 Strong: "Lack of segregation in affected members of two or more families." No segregation data demonstrating lack of segregation are available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to ACMG guidelines, BP1 Supporting: "Missense variant in a gene where only LOF variants cause disease." The variant is a LOF frameshift. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, BP2 Supporting: "Observed in trans with a pathogenic PTEN variant or in cis with multiple PTEN variants." No such observations exist. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to ACMG guidelines, BP3 Supporting: "In-frame indels in a repetitive region without known function." This is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, BP4 Supporting: "Multiple lines of computational evidence suggest no impact." Although SpliceAI score is low, the variant causes a frameshift leading to LOF. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, BP5 Supporting: "Variant found in a case with an alternate molecular basis for disease." No alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to ACMG guidelines, BP6 Supporting: "Reputable source reports variant as benign." No reputable benign classification is available. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, BP7 Supporting: "Synonymous or intronic variant at +7/-21 with no predicted splicing impact." This is a frameshift. Therefore, this criterion is not applied.