PTEN c.994A>T, p.Lys332Ter
NM_000314.8:c.994A>T
COSM6980925
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Pathogenic
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
2 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.994A>T
Protein Change
K332*
Location
Exon 8
(Exon 8 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM6980925
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
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
0 publications
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories).
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 K332* variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that expression of PTEN truncation mutations in mouse embryonic fibroblasts is oncogenic and increases genome fragility due to impaired chromosomal centromere association.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
mutationtaster: D
Benign:
CADD: 9.28
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines for PTEN: 'Very Strong Use PTEN PVS1 decision tree. PVS1 applied - truncating variant (exon information unavailable)'. The evidence shows that NM_000314.8:c.994A>T introduces a premature stop codon (K332*), a truncating event in a gene where loss‐of‐function is a known disease mechanism. Therefore, this criterion is applied at Very Strong strength.
PS3
PS3 (Not Applied)
Strength Modified
According to PTEN Pre-processing guidelines: 'High confidence not TRUE ("NAN"), PS3 rule not applied'. Although earlier functional studies were reported, the definitive PTEN-specific pre-processing finding indicates insufficient confidence to apply PS3. Therefore, PS3 is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to standard ACMG and VCEP guidelines for PM2: 'Absent in population Databases present at <0.00001 (0.001%) allele frequency'. The evidence for this variant shows it is not found in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength.
PP5
PP5 (Supporting)
According to standard ACMG guidelines: 'Reputable source recently reports variant as pathogenic'. The evidence indicates that ClinVar reports this variant as Pathogenic from a reputable clinical laboratory. Therefore, PP5 is applied at Supporting strength.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PS1 pertains to the same amino acid change as a previously established pathogenic variant regardless of nucleotide change'. The evidence does not show an alternative variant meeting this criterion. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PS2 applies for de novo occurrences with parental confirmation'. No de novo evidence is provided for this variant. Therefore, PS2 is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PS4 involves an increased prevalence of the variant in affected individuals compared to controls'. There is no case-control data provided for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PM1 is for variants located in a mutational hot spot and/or critical and well-established functional domain'. No evidence suggests this variant falls specifically within such a domain. Therefore, PM1 is not applied.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PM3 is used for recessive disorders when the variant is detected in trans with a pathogenic variant'. There is no evidence of a recessive inheritance context for this variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PM4 pertains to protein length changes due to in-frame indels or stop-loss variants'. This variant is a premature stop codon rather than an in-frame indel or stop-loss; thus, PM4 is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PM5 is for missense changes at an amino acid residue where a different pathogenic missense change has been seen before'. Since this variant is a nonsense change and not a missense change, PM5 is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PM6 involves assumed de novo occurrences without full confirmation'. There is no information concerning a de novo status for this variant. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PP1 is for co-segregation with disease in multiple affected family members'. There is no segregation data provided for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PP2 applies to missense variants in genes with a low rate of benign variation'. Since this variant is not missense, PP2 is not applicable and therefore not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PP3 is based on multiple lines of computational evidence supporting a deleterious effect'. Although some in silico tools were used, the computational evidence was mixed and does not strongly support a deleterious impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'PP4 is for a phenotype highly specific for a disease with a single genetic etiology'. There is no specific phenotype data provided that meets this criterion. Therefore, PP4 is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BA1 stands alone if the allele frequency is above a defined threshold'. The allele frequency for this variant is 0%, far below the BA1 threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BS1 applies when allele frequency is above the expected for the disorder'. Since this variant is absent from population databases, BS1 is not applicable. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BS2 is used when the variant is observed in homozygous state in a healthy individual'. There is no evidence of homozygous observations in unaffected individuals. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BS3 is applicable when well-established studies show no damaging effect on protein function'. There are no such studies indicating a benign impact for this variant. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BS4 relates to lack of segregation in affected members of families'. No segregation data contradicts pathogenicity for this variant. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BP1 is for variants where missense changes are less likely to be pathogenic in genes where truncating variants cause disease'. Since this variant is truncating, BP1 is not applicable. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BP2 applies when the variant is observed in trans with another pathogenic variant'. There is no evidence of such observations for this variant. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BP3 is for in-frame deletions/insertions in repetitive regions with no predicted impact'. This variant is not an in-frame event; hence, BP3 is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BP4 is based on multiple lines of computational evidence suggesting no impact on gene or gene product'. Although computational predictions provided mixed results, the PTEN pre-processing and overall evidence did not support a benign computational verdict. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BP5 is used when the variant is found in a case with an alternate molecular basis for disease'. There is no evidence supporting an alternative causative mechanism for the disease in this case. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BP6 refers to benign criteria based on reputable source assertion without available evidence'. There is no additional evidence to support BP6 for this variant. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines: 'BP7 applies to synonymous or intronic variants predicted to have no splicing impact'. Since this variant results in a premature stop codon, BP7 is not applicable. Therefore, BP7 is not applied.