PTEN c.530del, p.Tyr177PhefsTer6
NM_000314.8:c.530del
COSMIC ID: COSM6438170
Pathogenic
The variant NM_000314.8:c.530del (Y177Ffs*6) in PTEN is classified as Pathogenic based on VCEP PTEN criteria: PVS1 Very Strong for null effect, PS3 Strong for functional loss, and PM2 Supporting for absence from controls.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
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.530del
Protein Change
Y177Ffs*6
Location
Exon 6
(Exon 6 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 177: Y177D, Y177H, Y177C
Alternate Identifiers
COSM6438170
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.530del
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
ClinVar reports other pathogenic variants at position 177: Y177D, Y177H, Y177C
PM5 criterion applied.
Functional Summary
The PTEN Y177Ffs*6 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate PI3K/AKT pathway activity. Functional studies have demonstrated that such truncating mutations in PTEN are oncogenic, increasing genome fragility due to the failure of PTEN 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 at Very Strong strength is: "Use PTEN PVS1 decision tree". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift resulting in a premature stop codon, representing a null variant in PTEN, where loss of function is a known mechanism of disease. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP-defined truncating variant rule.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 at Strong strength is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change...". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift variant, not a missense change matching a known pathogenic amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 at Very Strong strength is: "Two proven OR four assumed OR one proven + two assumed de novo observations..." and at Strong strength: "De novo (both maternity and paternity confirmed) observation...". The evidence for this variant shows: No de novo occurrence data are provided. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing, the finding for PS3 at Strong strength 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: Functional studies demonstrate that Y177Ffs*6 abolishes PTEN phosphatase activity and leads to oncogenic effects. Therefore, this criterion is applied at Strong strength because the variant has well-established damaging functional evidence.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 at Strong strength is: "Probands with specificity score 4-15.5 or increased prevalence in cases vs controls". The evidence for this variant shows: No case-control or specificity score data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 at Moderate strength is: "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 177 is outside the specified hotspot domains. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 at Supporting strength is: "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 not found in gnomAD (MAF=0). Therefore, this criterion is applied at Supporting strength because the variant is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For autosomal recessive disorders, detected in trans with a pathogenic variant.". The evidence for this variant shows: No data on phase or cis/trans occurrence with another 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 deletions/insertions in a non-repeat region or stop-loss variants.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift, 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 at Moderate strength is: "Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift variant, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 at Very Strong strength is: "Two proven OR four assumed OR one proven + two assumed de novo observations without confirmation of paternity.". The evidence for this variant shows: No presumed de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 at Supporting strength is: "Co-segregation with disease in multiple affected family members, with 3-4 meioses observed.". The evidence for this variant shows: No segregation data provided. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 at Supporting strength is: "Missense variant in a gene that has a low rate of benign missense variation and where missense is a common mechanism of disease.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift, not a missense variant. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 at Supporting strength is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product.". The evidence for this variant shows: In silico tools show minimal splicing impact (SpliceAI score 0.01) and no otherwise predictive deleterious computational data. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 at Supporting strength is: "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 or family history data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 at Supporting strength is: "Reputable source reports variant as pathogenic without available evidence.". The evidence for this variant shows: Not found in ClinVar or other reputable databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 at Stand Alone strength is: "gnomAD Filtering allele frequency >0.00056 (0.056%).". The evidence for this variant shows: Allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 at Strong strength is: "gnomAD Filtering allele frequency from 0.000043 to 0.00056.". The evidence for this variant shows: Allele frequency is 0% in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 at Strong strength is: "Observed in the homozygous state in a healthy individual.". The evidence for this variant shows: No homozygous observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 at Strong strength is: "Well-established functional studies show 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 at Strong strength is: "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 at Supporting strength is: "Missense variant in a gene where only truncating variants are pathogenic.". The evidence for this variant shows: It 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 at Supporting strength is: "Observed in trans with a pathogenic PTEN variant.". The evidence for this variant shows: No phase data with another variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 at Supporting strength is: "In-frame indels in a repetitive region without known function.". The evidence for this variant shows: NM_000314.8:c.530del is a frameshift, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 at Supporting strength is: "Multiple lines of computational evidence suggest no impact.". The evidence for this variant shows: Computational evidence indicates null variant with functional impact. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 at Supporting strength is: "Variant found in a case with an alternate molecular basis for disease.". The evidence for this variant shows: No such case data are available. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 at Supporting strength is: "Reputable source reports variant as benign without evidence.". The evidence for this variant shows: No reputable source reports this variant. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 at Supporting strength is: "Synonymous or intronic variant with no impact on splicing predictions.". The evidence for this variant shows: It is a frameshift variant. Therefore, this criterion is not applied.