PTEN c.37A>T, p.Lys13Ter
NM_000314.8:c.37A>T
COSMIC ID: COSM86063
Pathogenic
This nonsense variant (K13*) in PTEN causes loss of function and meets PVS1 (Very Strong) and PS3 (Moderate) per PTEN-specific VCEP rules, with additional supporting evidence from population absence (PM2), ClinVar reports (PP5), and computational benign predictions (BP4), collectively justifying a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
BP4
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.37A>T
Protein Change
K13*
Location
Exon 1
(Exon 1 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM86063
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.37A>T
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
1 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in PTEN are known to be pathogenic (PMID: 9467011, 21194675). This sequence change creates a premature translational stop signal at codon 13 (p.Lys13*) of the PTEN gene. It is expected to result in an absent or disrupted protein product.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories).
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 K13* variant is a truncating mutation that results in a premature stop codon at amino acid 13, leading to a loss of PTEN phosphatase function. Functional studies indicate that this truncation impairs the protein's ability to negatively regulate the PI3K/AKT pathway and increases genomic instability due to disrupted chromosomal centromere association. Additionally, yeast assays demonstrate reduced phosphatase activity, supporting the conclusion that the PTEN K13* variant is functionally damaging and likely oncogenic.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 9.96
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence shows this variant is a nonsense change (K13*) introducing a premature stop codon in PTEN, not in the last exon, leading to loss of function. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP PVS1 decision tree for PTEN.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". There is no known variant causing the same amino acid change at codon 13. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Very Strong: two proven de novo or four assumed de novo, etc., in a patient with the disease and no family history". No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing: "Applied PS3_Moderate evidence added based on high-confidence functional score (-3.9912) < threshold (-1.11)". The evidence shows phosphatase activity of –3.9912, which is below the VCEP PTEN threshold of –1.11, indicating damaging effect. Therefore, this criterion is applied at Moderate strength.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Moderate: probands with specificity score 2–3.5 or increased prevalence in cases versus controls". 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: "Located in a mutational hot spot and/or critical and well-established functional domain (residues 90–94, 123–130, 166–168)". Codon 13 is outside these PTEN functional domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines: "Supporting: Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD". The variant is not found in gnomAD or other large population datasets. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: "Detected in trans with a pathogenic variant in recessive disorders". PTEN disease is dominant and no trans observations are relevant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines: "Protein length changes due to in-frame indels or stop-loss variants". This is a nonsense variant, not an in-frame alteration or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: "Missense change at an amino acid residue where a different missense change determined to be pathogenic". This is a nonsense variant, not missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines: "Assumed de novo without paternity/maternity confirmation". No de novo data exist. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines: "Co-segregation with disease in multiple affected family members". No segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG: "Missense variant in a gene with low benign missense variation". This is a nonsense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: multiple computational tools predict deleterious effect (REVEL>0.7 for missense; SpliceAI for splicing)". Computational evidence (CADD 9.96, SpliceAI 0.08) does not support a deleterious effect. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". No phenotype/family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG: "Supporting: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory". ClinVar lists this variant as Pathogenic by two submitters without primary data. Therefore, this criterion is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: "Stand Alone: gnomAD allele frequency >0.00056". The variant is absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: allele frequency 0.000043–0.00056". The variant is absent from population databases. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: observed homozygous in unaffected individual". No homozygous observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: well-established functional studies show no damaging effect". Functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: "Strong: lack of segregation in affected members of ≥2 families". No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines: "Missense in a gene where only truncating variants cause disease". This is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines: "Observed in cis/trans with a pathogenic variant for recessive inheritance". Not applicable to this dominant PTEN variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to VCEP guidelines: "In-frame indels in repetitive regions without known function". This is a nonsense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines: "Supporting: multiple computational tools suggest no impact". CADD is below pathogenic threshold (9.96) and SpliceAI score is low (0.08). Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines: "Supporting: variant found in a case with an alternate molecular basis for disease". No alternate molecular diagnosis information is provided. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG: "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: "Supporting: synonymous or intronic variant with no predicted splicing impact". This is a coding nonsense variant. Therefore, this criterion is not applied.