PTEN c.388C>T, p.Arg130Ter
NM_000314.8:c.388C>T
COSM5152
Population Frequency
0.00119%
Low Frequency
ClinVar Classification
Likely Pathogenic
12 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
167 occurrences
PM1 Criterion 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.388C>T
Protein Change
R130*
Location
Exon 5
(Exon 5 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5152
Variant interpretation based on transcript NM_000314.8
Clinical Evidence
Global Frequency
0.00119%
Rare
Highest in Population
South Asian
0.00327%
Rare
Global: 0.00119%
South Asian: 0.00327%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 251384
Alt: 3
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00119%, 3/251384 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00327%, 1/30614 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
12 publications
Likely Pathogenic
Based on 36 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
12 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (35 clinical laboratories) and as Likely pathogenic (1 clinical laboratories).
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
1176
Reported mutations in this domain
0
50
100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (1176 mutations).
PM1 criterion applied: Located in a mutational hot spot and/or critical and well-established functional domain.
Related Variants in This Domain
Functional Studies
Summary
The PTEN R130* variant results in a premature truncation of the protein, leading to a loss of function. Functional studies demonstrate that this variant is inactivating, as evidenced by its inability to suppress Akt phosphorylation, reduced protein stability, and loss of PTEN expression. Additionally, it acts as a dominant negative regulator of the PI3-AKT signaling pathway, decreases p53 signaling, and increases DNA damage and transformation ability in various models. These findings support a damaging effect of the PTEN R130* variant.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Neutral:
Show all
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to PTEN Pre-processing guidelines, the rule for PVS1 is: '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' and it is noted 'PVS1 applied - truncating variant (exon information unavailable)'. The evidence for this variant shows that NM_000314.8:c.388C>T (p.R130*) creates a premature stop codon, leading to loss of function. Therefore, this criterion is applied at Very Strong strength because a truncating variant in PTEN, where loss-of-function is established, meets the PVS1 criteria per the PTEN-specific decision tree.
PS3
PS3 (Moderate)
Strength Modified
According to PTEN Pre-processing guidelines, the rule for PS3 is: 'Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product' with the specific note 'Applied PS3_Moderate (Score -3.4881 < threshold (-1.11))'. The evidence for this variant shows that functional studies demonstrate loss of PTEN activity, inability to suppress Akt phosphorylation, reduced protein stability, and other damaging effects. Therefore, this criterion is applied at Moderate strength.
PM1
PM1 (Moderate)
According to VCEP guidelines for PTEN, the rule for PM1 is: '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'. The evidence for this variant shows that the p.R130* change occurs at residue 130, which is within the defined catalytic motif. Therefore, this criterion is applied at Moderate strength.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines for PM2, the rule is: 'Absent in population Databases present at <0.00001 (0.001%) allele frequency (Supporting)' with the modification that extremely rare alleles in large population databases support PM2. The evidence for this variant shows an allele frequency of 0.00119% (approximately 1.19e-05), which is extremely rare. Therefore, this criterion is applied at Supporting strength.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: '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 that it has been reported in ClinVar as Pathogenic by 35 clinical laboratories and as Likely Pathogenic by 1 laboratory. Therefore, this criterion is applied at Supporting strength.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change' but no such evidence is provided. The evidence for this variant does not include an alternative nucleotide change leading to the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) observation in a patient with the disease' but there is no de novo observation data provided for this variant. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls' but no case-control comparison data is available. The evidence does not support a significant enrichment in affected individuals. Therefore, this criterion is not applied.
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' and the evidence does not indicate a recessive inheritance mode or in trans occurrence. 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 deletions/insertions or stop-loss variants' but this variant is a nonsense variant leading to truncation and is covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before' but the variant in question is a truncating variant rather than a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity' with de novo evidence required. No such de novo evidence is provided. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members' but no familial segregation data is provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease' but the variant is a nonsense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product' but the computational predictions are mixed (CADD score modest and mutationtaster benign) and are less relevant for a truncating variant. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology' but no specific phenotype information is provided. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: 'Stand Alone filtering allele frequency >0.00056 (0.056%)' but the variant allele frequency is much lower. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%)' indicating benign evidence; however, the variant frequency is below this benign threshold. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Observed in the homozygous state in a healthy individual' but no homozygous observations with healthy status are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function' but the available functional data strongly supports a damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Lack of segregation in affected members of two or more families' but no segregation data is provided. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants are known to cause disease' but while PTEN does tolerate some missense variation, the variant in question is a nonsense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic or likely pathogenic variant or multiple observations in cis' but there is no data provided regarding allelic configuration. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions in repetitive regions without a known function' but this is not applicable to a truncating variant. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product' but in this case, the weight of evidence from well-established functional studies (PS3) and the nature of the truncating event override any computational evidence suggesting benign impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease' but there is no evidence provided of an alternate explanation. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation' but the reputable sources have reported this variant as pathogenic/likely pathogenic. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact' but this variant is not synonymous or intronic. Therefore, this criterion is not applied.