PTEN c.493_496del, p.Gly165Ter
NM_000314.8:c.493_496del
COSMIC ID: COSM5945765
Pathogenic
PTEN NM_000314.8:c.493_496del (G165*) is a truncating variant leading to loss of function, absent from controls, with strong computational and functional evidence of pathogenicity (PVS1, PS3_Moderate, PM2_Supporting, PP3_Supporting). These criteria collectively support a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
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.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
Genome Browser
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HGVS InputNM_000314:c.493_496del
Active Tracks
ConservationRefSeqClinVargnomAD
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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
Functional Summary
The PTEN G165* variant is a truncating mutation that results in a premature stop codon, leading to the production of a C-terminally truncated PTEN protein. Functional studies indicate that this truncation results in a loss of PTEN phosphatase activity, as demonstrated by reduced activity in a yeast assay. Additionally, expression of similar truncating mutations in mouse embryonic fibroblasts has shown oncogenic properties and increased genomic fragility due to impaired chromosomal centromere association. These findings support a damaging effect of the PTEN G165* variant.
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: it is a truncating (nonsense) variant leading to a premature stop codon (G165*) in PTEN, with loss-of-function as a known disease mechanism and not located in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant meets the PTEN decision tree for null variants.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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: there is no previously established pathogenic variant with the same amino acid change at G165. Therefore, this criterion 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." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Applied PS3_Moderate (Score -3.8545 < -1.11)". The evidence for this variant shows: a high-confidence functional score of –3.8545 in PTEN phosphatase assays demonstrating loss of function. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN-specific PS3 threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4–15.5 OR the prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case–control or proband specificity data are available. Therefore, this criterion 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 (NP_000305.3)." The evidence for this variant shows: the stop codon occurs at residue 165, which is adjacent but not within the defined catalytic motif residues 166–168. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: 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 absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Moderate Strength: Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: PTEN-related disease is autosomal dominant and no biallelic data are available. Therefore, this criterion 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." The evidence for this variant shows: it is a nonsense (truncating) variant, not an in-frame indel or stop-loss. Therefore, this criterion 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 or likely pathogenic has been seen before." The evidence for this variant shows: it is a nonsense variant, not a missense change. Therefore, this criterion 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 without confirmation of paternity/maternity." The evidence for this variant shows: no presumed de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong Strength: Co-segregation with disease in multiple affected family members (3–4 meioses for Supporting, 5–6 for Moderate, ≥7 for Strong)." The evidence for this variant shows: no familial segregation data are provided. Therefore, this criterion 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." The evidence for this variant shows: it is a truncating variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak. Missense variants: REVEL >0.7." The evidence for this variant shows: SpliceAI predicts acceptor loss with a maximum score of 0.99. Therefore, this criterion is applied at Supporting strength because computational tools predict a deleterious splicing impact.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Patient’s phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no specific phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source reports variant as pathogenic or likely pathogenic." The evidence for this variant shows: it is not found in ClinVar or other reputable databases. Therefore, this criterion 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 (0.056%)." The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion 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 evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion 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 individual." The evidence for this variant shows: no homozygous observations in healthy individuals are reported. Therefore, this criterion 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 show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging loss of PTEN activity. Therefore, this criterion 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." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense variant in a gene where truncating variants are known mechanism." The evidence for this variant shows: it is a truncating variant, not a missense variant. Therefore, this criterion 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." The evidence for this variant shows: no cis/trans phase data with another PTEN variant are available. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: it is a nonsense variant, not an in-frame indel. Therefore, this criterion 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." The evidence for this variant shows: computational predictions indicate a deleterious splicing effect. Therefore, this criterion 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." The evidence for this variant shows: no alternate molecular basis is reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign." The evidence for this variant shows: it is not reported as benign in any reputable database. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous variant with no predicted splicing impact." The evidence for this variant shows: it is a nonsense variant, not synonymous. Therefore, this criterion is not applied.