PTEN c.78_79insG, p.Tyr27ValfsTer17
NM_000314.8:c.78_79insG
Pathogenic
This frameshift variant Y27Vfs*17 in PTEN leads to a premature stop codon and loss of function, is absent from population databases, and is supported by strong functional evidence of damaging effect. PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting) combine to classify this variant as Pathogenic.
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.78_79insG
Protein Change
Y27Vfs*17
Location
Exon 1
(Exon 1 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 27: Y27N, Y27C, Y27S
Variant interpretation based on transcript NM_000314.8
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HGVS InputNM_000314:c.78_79insG
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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 27: Y27N, Y27C, Y27S
PM5 criterion applied.
Functional Summary
The PTEN Y27Vfs*17 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. Functional studies have demonstrated that such truncating mutations are oncogenic, increasing genomic fragility due to impaired chromosomal centromere association.
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: Use PTEN PVS1 decision tree. Null Variant in a gene where LOF is a known mechanism of disease." The evidence for this variant shows: NM_000314.8:c.78_79insG (Y27Vfs*17) is a frameshift leading to a premature stop codon early in the transcript, not in the last exon. Therefore, this criterion is applied at Very Strong strength because it is a null variant in PTEN where loss of function is a known disease mechanism and not in the last exon.
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: Y27Vfs*17 is a frameshift, 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 VCEP guidelines, the rule for PS2 is: "Very Strong/Strong: De novo observations in a patient with the disease and no family history (strength depends on confirmation)." The evidence for this variant shows: No de novo data are available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product." According to PTEN pre-processing, the finding for PS3 is: "The PTEN Y27Vfs*17 variant is a truncating mutation that results in the loss of PTEN phosphatase function, leading to oncogenic effects demonstrated in functional assays." The evidence for this variant shows: Functional studies demonstrate complete loss of PTEN phosphatase activity and oncogenic impact. Therefore, this criterion is applied at Strong strength because well-established assays show a damaging effect on PTEN function.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Very Strong/Strong/Moderate/Supporting: Increased prevalence in affected individuals or proband specificity score thresholds." The evidence for this variant shows: No case series 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 is: "Moderate: Located in a mutational hotspot or critical functional domain (residues 90-94, 123-130, 166-168)." The evidence for this variant shows: Y27Vfs*17 lies outside known critical PTEN domains. 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 at <0.00001 allele frequency in gnomAD or another large database." 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 large control datasets.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Moderate: Detected in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: No evidence of a recessive genotype or trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate: Protein length changes due to in-frame indels or stop-loss variants." The evidence for this variant shows: This is a frameshift leading to truncation, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: Novel missense at a residue where another missense change is pathogenic." The evidence for this variant shows: Y27Vfs*17 is a frameshift, not a missense. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Very Strong/Strong/Moderate: Assumed de novo observations without full confirmation." The evidence for this variant shows: No de novo information available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong: Co-segregation with disease in multiple affected family members." The evidence for this variant shows: No family 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 in a gene with low benign missense rate and where missense is common." The evidence for this variant shows: It is a frameshift. 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 (REVEL>0.7 for missense; SpliceAI/VarSeak for splicing)." The evidence for this variant shows: SpliceAI max score 0.12 (below threshold) and no high REVEL. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting: Phenotype or family history highly specific for a single gene disorder." The evidence for this variant shows: No phenotype data provided. 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 without available evidence." The evidence for this variant shows: No such reports. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: Allele frequency >0.00056 in gnomAD." The evidence for this variant shows: Not present in gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: Allele frequency 0.000043–0.00056 in gnomAD." The evidence for this variant shows: Not present in gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong/Supporting: Observed in homozygous state in healthy individuals." The evidence for this variant shows: No such 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 functional studies show no damaging effect." The evidence for this variant shows: Functional studies show 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 members." 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 in a gene where only truncating variants cause disease." The evidence for this variant shows: It 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 variant for a dominant disorder." The evidence for this variant shows: No such data. 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 repetitive regions without known function." The evidence for this variant shows: Frameshift outside repeat region. 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." The evidence for this variant shows: Computational tools are inconclusive but functional data show damaging effect. 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." 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 VCEP guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign without evidence." 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: Synonymous or intronic variant with no predicted splicing impact." The evidence for this variant shows: It is a frameshift. Therefore, this criterion is not applied.