PTEN c.802-5_802-2del, p.?
NM_000314.8:c.802-5_802-2del
Variant of Uncertain Significance (VUS)
The intronic PTEN c.802-5_802-2delTTTA variant is absent from population databases (PM2_Supporting) and in silico predictions (SpliceAI score=1.0) support a splicing impact (PP3_Supporting). No functional studies or clinical data are available to apply higher‐weight criteria. Per PTEN‐specific VCEP guidelines, PVS1 is not applicable to non‐canonical splice sites. The remaining criteria are not met or lack data. The overall classification remains VUS.
ACMG/AMP Criteria Applied
PM2
PP3
Genetic Information
Gene & Transcript Details
Gene
PTEN
Transcript
NM_000314.8
MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000010.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 9 exons | Forward |
| NM_000314.5 | Alternative | 9 exons | Forward |
| NM_000314.4 | Alternative | 9 exons | Forward |
| NM_000314.3 | Alternative | 9 exons | Forward |
| NM_000314.6 | Alternative | 9 exons | Forward |
Variant Details
HGVS Notation
NM_000314.8:c.802-5_802-2del
Protein Change
?
Location
Exon 7
(Exon 7 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Genome Browser
Loading genome browser...
HGVS InputNM_000314:c.802-5_802-2del
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines for PTEN PVS1: "Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows it is an intronic deletion at positions -5 to -2, outside the canonical +/−1,2 splice sites. Therefore, this criterion is not applied because the variant does not meet the canonical splice site requirement for PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines for PS1: "Strong Strength: Strong 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 for this variant shows it is an intronic deletion with no amino acid change and no known pathogenic splice variant at the exact nucleotides. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines for PS2: "Strong Strength: Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.". There is no information on de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing finding for PS3: "The PTEN 802-5_802-2del variant has not been functionally characterized.". The evidence for this variant shows no in vitro or in vivo functional studies. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines for PS4: "Strong Strength: Strong Probands with specificity score 4-15.5 or prevalence significantly increased in affected versus controls.". There are no case reports or proband specificity scores for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines for PM1: "Moderate Strength: 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 shows the variant is intronic and not within any PTEN catalytic motif. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines for PM2: "Supporting Strength: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.". The evidence for this variant shows a MAF of 0% in gnomAD. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to Standard ACMG for PM3: "Detected in trans with a pathogenic variant for a recessive disorder.". PTEN-related disease is autosomal dominant and no evidence of trans occurrence is reported. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines for PM4: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.". The evidence shows this is an intronic deletion without a predicted in-frame effect on protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines for PM5: "Moderate Strength: Moderate Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.". This variant is intronic and not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines for PM6: "Moderate Strength: Moderate Assumed de novo, but without confirmation of paternity and maternity.". There is no de novo evidence available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines for PP1: "Supporting Strength: Supporting Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.". There are no segregation data for this variant. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to Standard ACMG for PP2: "Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.". This is an intronic deletion, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines for PP3: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak.". The evidence for this variant shows a SpliceAI acceptor loss score of 1.0, indicating high likelihood of splicing disruption. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to Standard ACMG for PP4: "Supporting Patient’s phenotype or family history 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
PP5 (Not Applied) Strength Modified
According to Standard ACMG for PP5: "Supporting Reputable source reports variant as pathogenic without available evidence.". No such reports exist for this variant. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines for BA1: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%).". The evidence shows an allele frequency of 0% in gnomAD, below threshold. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines for BS1: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056.". The allele frequency is 0%, outside the BS1 range. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for BS2: "Strong Strength: 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
BS3 (Not Applied) Strength Modified
According to VCEP guidelines for BS3: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.". There are no functional studies demonstrating lack of effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines for BS4: "Strong Strength: Strong Lack of segregation in affected members of two or more families.". No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to Standard ACMG for BP1: "Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease.". This is an intronic deletion, not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines for BP2: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant.". There is no evidence of this variant in trans with another PTEN pathogenic variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to Standard ACMG for BP3: "Supporting In-frame deletions/insertions in a repetitive region without a known function.". This deletion is intronic and not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines for BP4: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak.". Computational evidence indicates a high splicing impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines for BP5: "Supporting Strength: Supporting Variant found in a case with an alternate molecular basis for disease.". No such case data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to Standard ACMG for BP6: "Supporting Reputable source reports variant as benign without available evidence.". No such reports exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines for BP7: "Supporting Strength: Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.". This variant is at positions -5 to -2, within the splice region and predicted to impact splicing. Therefore, this criterion is not applied.