PTEN c.493_496del, p.Gly165Ter
NM_000314.8:c.493_496del
COSM5945765
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
1 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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.493_496del
Protein Change
G165*
Location
Exon 6
(Exon 6 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5945765
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications
0 publications
Clinical Statement
COSMIC
COSMIC ID
COSM5945765
Recurrence
1 occurrences
PM1 Criteria
Not Applied
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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
Functional Studies
Summary
The PTEN G165* variant results in a premature truncation of the protein, leading to reduced phosphatase activity as demonstrated in a yeast assay. This functional evidence supports a damaging effect, indicating a loss of PTEN protein function.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: 'Very Strong Strength: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific'. The evidence for this variant shows it is a truncating variant (nonsense/frameshift) 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 results in loss of function consistent with the PTEN PVS1 decision tree.
PS1
PS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS1 is: '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 no previously established pathogenic variant at this amino acid. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.' There are no parental data available to assess de novo status. Therefore, PS2 is not applied.
PS3
PS3 (Moderate)
Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: 'Applied PS3_Moderate evidence based on high-confidence functional score (-3.8545) < threshold (-1.11)'. The evidence for this variant shows a functional score of -3.8545 indicating significantly reduced phosphatase activity in validated assays. Therefore, PS3 is applied at Moderate strength because the variant demonstrates a damaging effect on PTEN function.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: 'Very Strong Strength: Probands with specificity score ≥16; Strong Strength: specificity score 4–15.5; Moderate Strength: 2–3.5; Supporting Strength: 1–1.5.' There are no data on proband specificity or case-control frequency. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate Strength: 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.' The variant affects residue 165, which is outside the defined domain. Therefore, PM1 is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Absent in population Databases present at <0.00001 allele frequency in gnomAD or another large sequenced population.' The evidence for this variant shows it is absent from gnomAD (MAF = 0%). Therefore, PM2 is applied at Supporting strength because the variant is not present in population databases.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for a recessive disorder.' PTEN-related disorders are autosomal dominant and no cis/trans data are provided. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM4 is: 'Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants.' This variant is a frameshift/nonsense rather than an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM5 is: 'Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.' This variant is truncating, not missense, and no missense pathogenic change is at this position. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM6 is: 'Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations...; Strong Strength: Two presumed de novo...; Moderate Strength: Assumed de novo without confirmation.' No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP1 is: 'Supporting Strength: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.' No family segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP2 is: 'Supporting Strength: 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 variant is truncating, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: '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 shows a SpliceAI maximum score of 0.99 predicting a high impact on splicing. Therefore, PP3 is applied at Supporting strength because in silico models predict a deleterious effect.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting Phenotype specific for disease with single genetic etiology.' No detailed phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting Reputable source supports pathogenicity but the evidence is not available to the laboratory to perform an independent evaluation.' There is no such external source for this variant. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone Strength: gnomAD Filtering allele frequency >0.00056.' The variant is not present in gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong Strength: gnomAD Filtering allele frequency from 0.000043 up to 0.00056.' The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong Strength: Observed in the homozygous state in a healthy or PHTS-unaffected individual.' No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Strong Strength: Well-established in vitro or in vivo functional studies shows no damaging effect.' Functional studies demonstrate damage, not lack of effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Strong Strength: Lack of segregation in affected members of two or more families.' No segregation studies are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP1 is: 'Supporting Strength: Missense variant in gene where only loss-of-function is known mechanism.' This variant is truncating. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Supporting Strength: Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis...' No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP3 is: 'Supporting Strength: In-frame deletions/insertions in a repetitive region without functional impact.' This variant is frameshift. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: Multiple lines of computational evidence suggest no impact on gene or gene product.' In silico evidence predicts damage. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP5 is: 'Supporting Strength: Variant found in a case with an alternate molecular basis for disease.' No alternate molecular basis is reported. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Reputable source reports variant as benign.' No such report exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: 'Supporting Strength: Synonymous or intronic variant at or beyond +7/-21 with no splicing impact.' This variant is truncating. Therefore, BP7 is not applied.