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 802-18_802-17del variant has not been functionally characterized, and its biological significance remains unknown.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 63 bp |
| Donor Loss (DL) | 0.01 | 40 bp |
| Acceptor Gain (AG) | 0.0 | 20 bp |
| Donor Gain (DG) | 0.0 | 489 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to PTEN VCEP guidelines, the PVS1 rule is: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows it is a deep intronic deletion outside of canonical ±1/2 splice sites and does not create a null transcript via the PVS1 decision tree. Therefore, this criterion is not applied because the variant does not meet any PVS1 decision tree branch for loss of function.
PS1 (Not Applied)
According to standard ACMG guidelines, the PS1 rule is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows it is an intronic deletion and does not alter an amino acid. Therefore, this criterion is not applied because there is no amino acid change matching a known pathogenic variant.
PS2 (Not Applied)
According to standard ACMG guidelines, the PS2 rule is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows no information on de novo occurrence or parental testing. Therefore, this criterion is not applied due to lack of de novo data.
PS3 (Not Applied)
According to PTEN pre-processing, the finding for PS3 is: "The PTEN 802-18_802-17del variant has not been functionally characterized, and its biological significance remains unknown." The evidence for this variant shows no functional studies. Therefore, this criterion is not applied because no well-established functional assay data exist.
PS4 (Not Applied)
According to standard ACMG guidelines, the PS4 rule is: "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls." The evidence for this variant shows no case–control or proband data. Therefore, this criterion is not applied because there is no evidence of increased prevalence in cases.
PM1 (Not Applied)
According to VCEP guidelines, the PM1 rule 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 (NP_000305.3)." The evidence for this variant shows it is an intronic deletion outside of any defined PTEN functional domain. Therefore, this criterion is not applied.
PM2 (Supporting)
According to VCEP guidelines, the PM2 rule is: "Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%)." The evidence for this variant shows it is not found in gnomAD or other control databases (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3 (Not Applied)
According to standard ACMG guidelines, the PM3 rule is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows PTEN disease is autosomal dominant and there is no in trans observation. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the PM4 rule is: "Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif (see PM1), and variants causing protein extension." The evidence for this variant shows it is an intronic deletion not affecting coding sequence. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the PM5 rule 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. In addition, variant being interrogated must have BLOSUM62 score equal to or less than the known variant." The evidence for this variant shows it is not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the PM6 rule is: "Moderate Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history." The evidence for this variant shows no de novo or family history data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the PP1 rule 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 PP2 rule is: "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 this variant shows it is intronic, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the PP3 rule is: "Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak Missense variants: REVEL score > 0.7." The evidence for this variant shows SpliceAI max score 0.01 and no deleterious predictions. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the PP4 rule is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The evidence for this variant shows no clinical phenotype or family history provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the PP5 rule is: "Reputable source reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows no reputable pathogenic assertion. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the BA1 rule 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 BS1 rule is: "Strong gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)." The evidence for this variant shows allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the BS2 rule is: "Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual. One observation if homozygous status confirmed, two if not confirmed." The evidence for this variant shows no homozygous observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the BS3 rule is: "Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. To be applied to intronic or synonymous variants, RNA, mini-gene or other splicing assay demonstrating no splicing impact." The evidence for this variant shows no such functional splicing assays. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the BS4 rule is: "Strong Lack of segregation in affected members of two or more families." The evidence for this variant shows no segregation information. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the BP1 rule is: "Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows it is intronic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the BP2 rule is: "Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants." The evidence for this variant shows no in cis or in trans observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the BP3 rule is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows an intronic deletion outside of a repetitive coding region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the BP4 rule is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak Missense variants: REVEL scores < 0.5." The evidence for this variant shows SpliceAI predicts no splice impact (max score 0.01) and no deleterious computational predictions. Therefore, this criterion is applied at Supporting strength because multiple in silico tools predict no functional effect.
BP5 (Not Applied)
According to VCEP guidelines, the BP5 rule is: "Supporting Variant found in a case with an alternate molecular basis for disease. Other gene/disorder must be considered highly penetrant AND patient’s personal/family history must demonstrate no overlap between other gene and PTEN." The evidence for this variant shows no such case with an alternate molecular basis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the BP6 rule is: "Reputable source reports variant as benign." The evidence for this variant shows no reputable benign assertion. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the BP7 rule is: "Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice." The evidence for this variant shows it lies at -19 to -18, which is within the -21 to -1 region, not beyond -21. Therefore, this criterion is not applied.