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
OpenThis sequence change affects a donor splice site in intron 7 of the PTEN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Cowden syndrome (PMID: 9600246, 10234502, 11238682). ClinVar contains an entry for this variant (Variation ID: 933785). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9600246, 11071384). For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.57 | -167 bp |
| Donor Loss (DL) | 1.0 | -1 bp |
| Acceptor Gain (AG) | 0.04 | -311 bp |
| Donor Gain (DG) | 0.28 | 74 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 at Very Strong strength is: 'Null Variant (splicing +1/2) in a gene where loss of function is a known mechanism of disease; Use PTEN PVS1 decision tree'. The evidence shows this variant affects the canonical +1 splice donor site predicted to abolish normal splicing in PTEN. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for canonical splice site variants in a loss-of-function gene.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 at Strong strength 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 shows no previously reported pathogenic variant at the same nucleotide position. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 at Strong strength is: 'De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history'. The evidence shows no de novo data. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to PTEN pre-processing, PS3 functional evidence: 'The variant has not been functionally characterized'. Therefore, PS3 is not applied at any strength due to absence of functional assay data.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 at Strong strength is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls'. The evidence shows no case-control or phenotype specificity data. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 at Moderate strength is: 'Located in a mutational hotspot and/or critical and well-established functional domain, including residues in catalytic motifs 90-94, 123-130, 166-168'. The evidence shows the variant affects the splice site at position +1 outside these motifs. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 at Supporting strength is: 'Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD'. The evidence shows this variant is not present in gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 at Moderate strength is: 'For recessive disorders, detected in trans with a pathogenic variant'. PTEN is an autosomal dominant gene, so PM3 is not applicable and not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 at Moderate strength is: 'Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants'. The evidence shows a splice site variant, not an in-frame indel. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 at Moderate strength is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before'. The evidence is a splice variant, not missense. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 at Moderate strength is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence shows no de novo assumptions. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 at Supporting strength is: 'Co-segregation with disease in multiple affected family members, with 3–4 meioses observed'. No segregation data provided. Therefore, PP1 is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 at Supporting strength 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 variant is a splice site change. Therefore, PP2 is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 at Supporting strength is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product (SpliceAI and VarSeak concordance)'. The evidence shows SpliceAI predicts donor loss with a maximum score of 1.0. Therefore, PP3 is applied at Supporting strength.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 at Supporting strength is: 'Patient’s phenotype is highly specific for a disease with a single genetic etiology'. No phenotype information provided. Therefore, PP4 is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 at Supporting strength is: 'Reputable source reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation'. ClinVar lists this variant as Pathogenic from one clinical laboratory. Therefore, PP5 is applied at Supporting strength.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 at Stand Alone strength is: 'gnomAD Filtering allele frequency >0.00056'. The variant has 0% frequency in gnomAD. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 at Strong strength is: 'gnomAD Filtering allele frequency from 0.000043 up to 0.00056'. The variant has 0% frequency in gnomAD. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 at Strong strength is: 'Observed in the homozygous state in a healthy or PHTS-unaffected individual'. No homozygous observations reported. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 at Strong strength is: 'Well-established in vitro or in vivo functional studies show no damaging effect'. No functional studies demonstrating lack of effect are available. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 at Strong strength is: 'Lack of segregation in affected members of two or more families'. No segregation data provided. Therefore, BS4 is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 at Supporting strength is: 'Missense variant in a gene where only loss of function causes disease'. The variant is a splice site change. Therefore, BP1 is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 at Supporting strength is: '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'. No trans/cis data. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 at Supporting strength is: 'In-frame insertions/deletions in a repetitive region without predicted impact'. The variant is a splice site change, not an in-frame indel. Therefore, BP3 is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 at Supporting strength is: 'Multiple lines of computational evidence suggest no impact'. The evidence shows SpliceAI predicts a high‐impact splice donor loss. Therefore, BP4 is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 at Supporting strength is: 'Variant found in a case with an alternate molecular basis for disease'. No alternate molecular basis is reported. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 at Supporting strength is: 'Reputable source reports variant as benign but the evidence is not available'. No reputable source reports this variant as benign. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 at Supporting strength is: 'A synonymous or intronic variant at or beyond +7/-21 with no predicted splicing impact'. This variant is at +1. Therefore, BP7 is not applied.