PTEN c.265_266del, p.Pro89PhefsTer2
NM_000314.8:c.265_266del
Pathogenic
This PTEN frameshift variant (P89Ffs*2) produces loss of function in a gene where LOF is disease mechanism, supported by very strong PVS1, strong PS3 functional studies, and supporting PM2 (absent from controls) and PP5 (ClinVar Pathogenic assertion), fulfilling criteria for a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
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.265_266del
Protein Change
P89Ffs*2
Location
Exon 5
(Exon 5 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 89 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.265_266del
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
No evidence of other pathogenic variants at position 89 in gene PTEN
Functional Summary
The PTEN P89Ffs*2 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 expression of PTEN truncation mutations in mouse embryonic fibroblasts leads to oncogenic effects and increased genomic instability due to the inability of the truncated protein to associate 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
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. Modification Type: Disease-specific". The evidence for this variant shows a frameshift (c.265_266del, P89Ffs*2) leading to a premature stop codon in PTEN, a gene where loss‐of‐function is a known mechanism of disease, and the variant is not in the last exon. Therefore, this criterion is applied at Very Strong strength because this is a null variant in a LOF gene per the PTEN decision tree.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "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." The evidence for this variant shows a frameshift leading to a novel stop, not the same amino acid change as any known pathogenic variant. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "Very Strong: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history; Strong: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." There are no data on de novo occurrence for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP 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." The evidence for this variant shows that PTEN P89Ffs*2 truncation abolishes phosphatase activity and leads to oncogenic effects and genomic instability in mouse embryonic fibroblasts. Therefore, this criterion is applied at Strong strength because well-established functional studies demonstrate a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs controls; Very Strong: specificity score ≥16." There are 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: Located in a mutational hot spot and/or critical and well-established functional domain, including residues in catalytic motifs 90-94, 123-130, 166-168." The variant is a frameshift outside of a defined missense hotspot. Therefore, this criterion is not applied.
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 or another large sequenced population." 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 population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Moderate: Detected in trans with a pathogenic variant in recessive disorders; Supporting: detected in cis or phase unknown with multiple pathogenic variants." PTEN disorders are dominant and no data on trans configuration. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Moderate: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The variant is a frameshift causing truncation, covered by PVS1. 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 a residue where a different missense change is pathogenic." This is a frameshift, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Very Strong/Strong/Moderate based on unconfirmed de novo observations." There are no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong based on co-segregation data." There are 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 with low benign missense rate and missense is common mechanism." This is a frameshift LOF 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 on the gene or gene product (missense REVEL >0.7; splicing concordance)." For this frameshift, in silico splice prediction shows minimal splicing impact and computational tools are not relevant to LOF. 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." Phenotypic data are not 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 evidence is not available for independent evaluation." The evidence for this variant shows ClinVar classification as Pathogenic by one clinical laboratory without available supporting data. 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: gnomAD Filtering allele frequency >0.00056 (0.056%)." The 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/Supporting: Allele frequency between specified thresholds up to 0.056%." The 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/Supporting: Observed homozygous in healthy individuals." There are 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/Supporting: Well-established functional studies show no damaging effect." 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/Supporting: Lack of segregation in affected individuals." No segregation data available. 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 gene where only truncating variants cause disease." This variant is truncating. 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 PTEN variant or multiple in cis." No phase or allelic data available. 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 indels in a repetitive region without functional impact." This variant is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: Multiple lines of computational evidence suggest no impact." Computational splice predictions show minimal effect but LOF mechanism predominates. Therefore, this criterion is not applied.
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." No alternate molecular basis data. 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 without evidence." No benign assertions exist. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: Synonymous or intronic variant beyond splice consensus with no predicted impact." This is a frameshift affecting coding sequence. Therefore, this criterion is not applied.