PTEN c.1030A>T, p.Lys344Ter
NM_000314.8:c.1030A>T
COSMIC ID: COSM6911165
Pathogenic
This PTEN nonsense variant c.1030A>T (K344*) is a loss-of-function change in a gene where truncating variants cause disease (PVS1 Very Strong), absent from population databases (PM2 Supporting), reported as pathogenic by a reputable source (PP5 Supporting), and shows benign computational predictions (BP4 Supporting). The combination of one Very Strong and three Supporting criteria yields a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
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.1030A>T
Protein Change
K344*
Location
Exon 9
(Exon 9 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM6911165
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.1030A>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
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 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 K344* variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have demonstrated that such truncating mutations are oncogenic, increasing genome fragility and impairing PTEN's association with chromosomal centromeres. This evidence supports a damaging effect of the variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 9.26
Neutral: Show all
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**: Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: NM_000314.8:c.1030A>T is a predicted truncating (nonsense) variant in PTEN, a gene where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it meets the PTEN-specific PVS1 decision tree for a null variant.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "**Strong Strength**: 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...". The evidence for this variant shows: the K344* change has no previously established pathogenic variant producing the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "**Very Strong Strength**: Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations...". The evidence for this variant shows: no de novo occurrences have been reported. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Result: High confidence not TRUE ('NAN'), PS3 rule not applied". The evidence for this variant shows: pre-processing did not meet the PTEN-specific functional assay confidence thresholds. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "**Strong Strength**: Strong Probands with specificity score 4-15.5 OR significant increase in affected vs 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**: Moderate Located in a mutational hot spot and/or critical and well-established functional domain (residues 90-94,123-130,166-168)...". The evidence for this variant shows: position K344 lies outside defined PTEN hotspot or functional motif. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "**Supporting Strength**: Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD...". The evidence for this variant shows: not present in gnomAD or other large population datasets. Therefore, this criterion is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant...". The evidence for this variant shows: no information on trans observations with another pathogenic PTEN variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame indels in a non-repeat region or stop-loss variants...". The evidence for this variant shows: this is a nonsense change, 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**: Moderate 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 a nonsense change, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "**Moderate Strength**: Moderate Assumed de novo but without confirmation...". 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 Strength**: Supporting 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 that has a low rate of benign missense variation...". The evidence for this variant shows: it is a nonsense variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Multiple lines of computational evidence support a deleterious effect... REVEL > 0.7 or concordant splicing predictions.". The evidence for this variant shows: in silico scores are mixed/benign (CADD 9.26, SpliceAI 0.04). Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.". The evidence for this variant shows: no detailed phenotype information provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: ClinVar entry classified as Pathogenic by one clinical laboratory. Therefore, this criterion is applied at Supporting strength.
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: allele frequency = 0%. 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: allele frequency = 0%. 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 or PHTS-unaffected individual...". The evidence for this variant shows: no such observations. 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 functional studies show no damaging effect on protein function...". The evidence for this variant shows: functional data support damaging effect, not lack of effect. 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. 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 are known to cause disease.". The evidence for this variant shows: this is a truncating variant, 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 or likely pathogenic PTEN variant...". 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: this is a nonsense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting Multiple lines of computational evidence suggest no impact on gene or gene product.". The evidence for this variant shows: in silico tools yield mixed/benign results and SpliceAI score is low. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP 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 Reputable source recently reports variant as benign...". The evidence for this variant shows: no reputable benign classification. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting A synonymous or intronic variant at or beyond +7/-21 with no splice impact.". The evidence for this variant shows: this is a nonsense variant, not synonymous or intronic. Therefore, this criterion is not applied.