PTEN c.807_808del, p.Lys269AsnfsTer28
NM_000314.8:c.807_808del
COSMIC ID: COSM6924959
Pathogenic
This frameshift variant in PTEN leads to loss of function, is absent from population databases, and has strong functional evidence of pathogenicity. Combined PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting) support a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.807_808del
Protein Change
K269Nfs*28
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 269 in gene PTEN
Alternate Identifiers
COSM6924959
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.807_808del
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
Unknown
Publications (0)
No publication details.
Clinical Statement
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
No evidence of other pathogenic variants at position 269 in gene PTEN
Functional Summary
The PTEN K269Nfs*28 variant is a truncating mutation that results in the loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Functional studies have shown that such truncating mutations are oncogenic, leading to increased genome fragility and an inability to associate with chromosomal centromeres.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
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." The evidence for this variant shows: NM_000314.8:c.807_808del (K269Nfs*28) is a frameshift resulting in a premature stop codon, in a gene where loss of function is a known mechanism of disease, and it is not in the last exon. Therefore, this criterion is applied at Very Strong strength because the variant is a null truncating alteration consistent with the PTEN PVS1 decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." The evidence for this variant shows: no previously established pathogenic variant results in the same amino acid change at position K269. Therefore, this criterion is not applied because there is no matching pathogenic amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 is: "The PTEN K269Nfs*28 variant is a truncating mutation that results in the loss of PTEN phosphatase function... Functional studies have shown that such truncating mutations are oncogenic..." The evidence for this variant shows: well-established in vitro/in vivo functional studies demonstrate a damaging effect on PTEN function. Therefore, this criterion is applied at Strong strength because functional assays support a damaging effect as per PTEN-specific PS3 guidance.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls OR probands with specificity score 4–15.5." The evidence for this variant shows: no case-control or proband specificity data are available. Therefore, this criterion is not applied due to lack of prevalence or specificity data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Located in a mutational hot spot and/or critical and well-established functional domain... catalytic motifs: 90–94, 123–130, 166–168." The evidence for this variant shows: position 269 is outside defined PTEN catalytic motifs. Therefore, this criterion is not applied because the variant does not lie in a hot spot or defined domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD..." The evidence for this variant shows: it is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large control populations.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 applies to recessive inheritance in trans observations. The evidence for this variant shows: no trans observations with another PTEN pathogenic variant. Therefore, this criterion is not applied because PM3 is not relevant for this dominant gene and no trans data are available.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame deletions/insertions..." The evidence for this variant shows: it is a frameshift, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "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: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate Assumed de novo, but without confirmation of paternity and maternity..." 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 Co-segregation with disease in multiple affected family members..." The evidence for this variant shows: no segregation data. 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 frameshift, not a 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..." The evidence for this variant shows: SpliceAI maximum score is 0.02 indicating minimal splicing impact and no deleterious in silico predictions. Therefore, this criterion is not applied due to lack of computational support for deleterious effect.
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 data specific to PTEN-related disorders. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source reports variant as pathogenic..." The evidence for this variant shows: not found in ClinVar or other reputable sources. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong gnomAD Filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Observed in the homozygous state in a healthy or PHTS-unaffected individual..." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "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. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "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.
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 cause disease." The evidence for this variant shows: it is truncating, 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..." The evidence for this variant shows: not in a repeat region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product..." The evidence for this variant shows: SpliceAI maximum score of 0.02 indicating minimal splicing impact. Therefore, this criterion is applied at Supporting strength because computational data support no significant effect.
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 reports variant as benign." The evidence for this variant shows: no such reports. 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 predicted splice impact." The evidence for this variant shows: it is a frameshift, not synonymous/intronic. Therefore, this criterion is not applied.