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 K269Nfs*28 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, leading to increased genome fragility and an inability to associate with chromosomal centromeres.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.02 | 41 bp |
| Donor Loss (DL) | 0.0 | -92 bp |
| Acceptor Gain (AG) | 0.0 | -2 bp |
| Donor Gain (DG) | 0.0 | 18 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: NM_000314.8:c.807_808del (K269Nfs*28) is a frameshift resulting in a premature stop codon, in a gene where loss of function is a known mechanism of disease, and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant is a null truncating alteration consistent with the PTEN PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." The evidence for this variant shows: no previously established pathogenic variant results in the same amino acid change at position K269. Therefore, this criterion is not applied because there is no matching pathogenic amino acid change.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong 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 occurrence data are available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 is: "The PTEN K269Nfs*28 variant is a truncating mutation that results in the loss of PTEN phosphatase function... Functional studies have shown that such truncating mutations are oncogenic..." The evidence for this variant shows: well-established in vitro/in vivo functional studies demonstrate a damaging effect on PTEN function. Therefore, this criterion is applied at Strong strength because functional assays support a damaging effect as per PTEN-specific PS3 guidance.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls OR probands with specificity score 4–15.5." The evidence for this variant shows: no case-control or proband specificity data are available. Therefore, this criterion is not applied due to lack of prevalence or specificity data.
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... catalytic motifs: 90–94, 123–130, 166–168." The evidence for this variant shows: position 269 is outside defined PTEN catalytic motifs. Therefore, this criterion is not applied because the variant does not lie in a hot spot or defined domain.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD..." 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 large control populations.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 applies to recessive inheritance in trans observations. The evidence for this variant shows: no trans observations with another PTEN pathogenic variant. Therefore, this criterion is not applied because PM3 is not relevant for this dominant gene and no trans data are available.
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: it is a frameshift, 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 has been seen before..." The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Moderate Assumed de novo, but without confirmation of paternity and maternity..." The evidence for this variant shows: no de novo data reported. 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..." 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..." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect..." The evidence for this variant shows: SpliceAI maximum score is 0.02 indicating minimal splicing impact and no deleterious in silico predictions. Therefore, this criterion is not applied due to lack of computational support for 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 phenotype data specific to PTEN-related disorders. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic..." 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: "Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." 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 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 demonstrate damaging effect. 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 cause disease." The evidence for this variant shows: it is truncating, not missense. 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..." 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..." The evidence for this variant shows: not in a repeat region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product..." The evidence for this variant shows: SpliceAI maximum score of 0.02 indicating minimal splicing impact. Therefore, this criterion is applied at Supporting strength because computational data support no significant effect.
BP5 (Not Applied)
According to VCEP 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 molecular basis reported. 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." The evidence for this variant shows: no such reports. 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 splice impact." The evidence for this variant shows: it is a frameshift, not synonymous/intronic. Therefore, this criterion is not applied.