PTEN c.786_787insT, p.Lys263Ter
NM_000314.8:c.786_787insT
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Unknown
0 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 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.786_787insT
Protein Change
K263*
Location
Exon 7
(Exon 7 of 9)
5'
Exon Structure (9 total)
3'
Functional Consequence
Loss of Function
Related Variants
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 K263* variant is a truncating mutation that results in a premature stop codon, leading to the production of a truncated PTEN protein. Functional studies indicate that this truncation results in reduced phosphatase activity, as demonstrated in a yeast assay, and is associated with a loss of PTEN protein function. This loss of function impairs the protein's ability to negatively regulate the PI3K/AKT pathway and increases genomic instability, supporting its damaging effect.
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. Modification Type: Disease-specific". The evidence for this variant shows: c.786_787insT introduces a premature stop codon (K263*), creating a null allele in PTEN where LOF is a known disease mechanism, and it is not located in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant 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, where in silico models predict impact equal to or greater than the known pathogenic variant. Modification Type: Disease-specific". The evidence for this variant shows: no previously established pathogenic variant at amino acid K263 or identical amino acid change. Therefore, this criterion is not applied because there is no matching known pathogenic variant at this residue.
PS2
PS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Very Strong Strength: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history. Modification Type: Strength". The evidence for this variant shows: no reported de novo observations with confirmed maternity and paternity. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Moderate)
Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "Applied PS3_Moderate (Score -4.0440 < -1.11)". The evidence for this variant shows: functional assays demonstrate that the K263* truncation reduces PTEN phosphatase activity (score -4.0440) below the VCEP threshold of -1.11. Therefore, this criterion is applied at Moderate strength because the phosphatase activity meets the PTEN-specific PS3_moderate threshold.
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 The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Modification Type: Strength". The evidence for this variant shows: no case/control or specificity score data reported. Therefore, this criterion is not applied due to absence of case prevalence data.
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. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168. Modification Type: Disease-specific". The evidence for this variant shows: residue K263 is outside defined PTEN catalytic motifs. Therefore, this criterion is not applied because the variant is not located in a known hot spot or critical domain.
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 or another large sequenced population. If multiple alleles are present within any subpopulation, allele frequency in that subpopulation must be <0.00002 (0.002%). Modification Type: Disease-specific". The evidence for this variant shows: not found in gnomAD or other population databases (MAF=0%). 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: "For recessive disorders, detected in trans with a pathogenic variant in a patient with the disease.". The evidence for this variant shows: PTEN-related disease is dominant and no in trans data with another allele. Therefore, this criterion is not applied due to lack of relevant recessive inheritance evidence.
PM4
PM4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif, and variants causing protein extension. Modification Type: Disease-specific". The evidence for this variant shows: c.786_787insT causes a frameshift leading to truncation, not an in-frame change. Therefore, this criterion is not applied because it does not meet in-frame protein length change criteria.
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 or likely pathogenic has been seen before...". The evidence for this variant shows: it is not a missense change but a truncating insertion. Therefore, this criterion is not applied because the variant type does not match missense.
PM6
PM6 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate Strength: Moderate Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history. Modification Type: None". The evidence for this variant shows: no de novo data reported. Therefore, this criterion is not applied due to lack of assumed de novo evidence.
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, with 3 or 4 meioses observed. Modification Type: Disease-specific". The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied due to absence of familial segregation evidence.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Supporting Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.". The evidence for this variant shows: it is not a missense variant. Therefore, this criterion is not applied because the variant type does not meet PP2 requirements.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAl and VarSeak; Missense variants: REVEL score > 0.7. Modification Type: Disease-specific". The evidence for this variant shows: insufficient computational evidence of deleterious effect (SpliceAI score 0.03 minimal and no REVEL data). Therefore, this criterion is not applied due to lack of supportive computational predictions.
PP4
PP4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Supporting Patient’s phenotype is highly specific for a disease with a single genetic etiology.". The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied due to absence of clinical phenotype correlation.
PP5
PP5 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Supporting A variant is reported as pathogenic by a reputable source without shared data.". The evidence for this variant shows: not reported in ClinVar or other sources. Therefore, this criterion is not applied due to lack of external pathogenic assertions.
BA1
BA1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%). Modification Type: Disease-specific". The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied because the frequency is below the BA1 threshold.
BS1
BS1 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056. Modification Type: Disease-specific". The evidence for this variant shows: allele frequency is 0% in gnomAD. Therefore, this criterion is not applied because the frequency does not meet BS1 minimum.
BS2
BS2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual...". The evidence for this variant shows: no homozygous observations in healthy individuals. Therefore, this criterion is not applied due to absence of such observations.
BS3
BS3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Strong Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.". The evidence for this variant shows: functional studies demonstrate damaging effect (loss of phosphatase activity). Therefore, this criterion is not applied because the variant is damaging.
BS4
BS4 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong 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 due to absence of segregation studies.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Supporting Missense variant in a gene for which truncating variants are a common mechanism of disease.". The evidence for this variant shows: it is truncating, not missense. Therefore, this criterion is not applied because the variant type does not meet BP1 criteria.
BP2
BP2 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.". The evidence for this variant shows: no cis or trans observations with other PTEN variants. Therefore, this criterion is not applied due to lack of such data.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: Supporting In-frame deletions/insertions in a repetitive region without a known function.". The evidence for this variant shows: c.786_787insT causes a frameshift leading to truncation, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied because the variant does not meet BP3 conditions.
BP4
BP4 (Not Applied)
Strength Modified
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. Splicing variants: Concordance of SpliceAl and VarSeak; Missense variants: REVEL scores < 0.5.". The evidence for this variant shows: computational data are limited and the variant effect is truncating, not purely splicing, so no supportive benign computational evidence. Therefore, this criterion is not applied due to lack of relevant computational support for no impact.
BP5
BP5 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: 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 due to absence of alternate etiology.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Supporting A variant is reported as benign by a reputable source without available evidence.". The evidence for this variant shows: not reported elsewhere as benign. Therefore, this criterion is not applied due to lack of external benign assertions.
BP7
BP7 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Supporting A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact.". The evidence for this variant shows: it is a truncating coding variant, not synonymous or intronic. Therefore, this criterion is not applied because it does not meet BP7 requirements.