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
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 is a truncating mutation that results in a premature stop codon, leading to a loss of PTEN phosphatase function. Functional studies indicate that this variant reduces phosphatase activity, impairs the ability to negatively regulate the PI3K/AKT pathway, and increases genomic instability due to disrupted chromosomal centromere association. These findings support a damaging effect of the PTEN G165* variant.
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." The evidence for this variant shows: a truncating nonsense variant (G165*) in PTEN leading to a premature stop and loss of function; PTEN loss of function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength because the variant meets the PTEN PVS1 decision tree for null variants.
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 with the same amino acid change at this position. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." The evidence for this variant shows: no confirmed de novo observations reported. Therefore, this criterion is not applied.
PS3
PS3 (Moderate)
Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Score -3.8545 < -1.11 per Mighell et al. 2018, applying PS3 at Moderate strength." The evidence for this variant shows: well-established in vitro functional studies demonstrating significantly reduced phosphatase activity and disrupted pathway regulation. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN-specific PS3_moderate threshold.
PS4
PS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: Probands with specificity score 4-15.5 OR prevalence significantly increased in affected individuals compared with controls." The evidence for this variant shows: no case–control or proband specificity data 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 hotspot and/or critical and well-established functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: residue G165 is not within the specified catalytic motif regions. 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 allele frequency in gnomAD or another large sequenced population." The evidence for this variant shows: MAF=0% (not found in gnomAD). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: PTEN-associated disorders are autosomal dominant, and no trans data are relevant. 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." The evidence for this variant shows: the variant is a frameshift/nonsense, not an in-frame change. 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 has been seen before." The evidence for this variant shows: this is not a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate Strength: Assumed de novo without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data reported. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong: Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with low rate of benign missense variation and where missense variants are common mechanism." The evidence for this variant shows: this is not a missense variant. Therefore, this criterion 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 (SpliceAI score high)." The evidence for this variant shows: SpliceAI predicts a high impact (score 0.99) on splicing. Therefore, this criterion is applied at Supporting strength because computational tools concordantly predict deleterious effect.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting: Patient’s phenotype or family history highly specific for a disease with single genetic etiology." The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic without available evidence." The evidence for this variant shows: no such assertions. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: gnomAD filtering allele frequency >0.00056." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: gnomAD filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: Observed in homozygous state in a healthy individual." The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong: Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting: Missense variant in a gene for which primarily truncating variants cause disease." The evidence for this variant shows: the variant is truncating, not missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic PTEN variant OR multiple observations in cis." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: the variant is not in a repetitive region and is frameshifting. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: computational evidence predicts deleterious effect. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Supporting: Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Non–laboratory assertion of benign impact." The evidence for this variant shows: no such assertions. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: Synonymous or intronic variant beyond +7/-21 with no splicing impact." The evidence for this variant shows: it is a coding truncating variant. Therefore, this criterion is not applied.