PTEN c.227_228del, p.Tyr76Ter
NM_000314.8:c.227_228del
COSMIC ID: COSM4963
Pathogenic
This variant is classified as Pathogenic based on PVS1 (Very Strong) for a truncating loss-of-function in PTEN, PS3 (Moderate) for well-established functional impairment, PM2 (Supporting) for absence from population databases, and PP5 (Supporting) for multiple ClinVar pathogenic reports, meeting 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.227_228del
Protein Change
Y76*
Location
Exon 4
(Exon 4 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM4963
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.227_228del
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
Likely Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
2 Path
1 LP
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 clinical laboratories) and as Likely 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
Functional Summary
The PTEN Y76* variant is a truncating mutation that results in the premature termination of the PTEN protein, leading to a loss of its phosphatase function. Functional studies demonstrate that this truncation impairs PTEN's ability to negatively regulate the PI3K/AKT pathway and reduces its phosphatase activity, as evidenced by assays in yeast and mouse embryonic fibroblasts. This loss of function is associated with oncogenic properties, including increased genome fragility and 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 Very Strong is: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows it is a truncating (nonsense) variant leading to a premature stop codon early in the gene (not in the last exon) 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 PTEN-specific PVS1 decision tree for loss‐of‐function variants.
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 shows this variant results in a novel truncation (Y76*) and no identical amino acid change has previously been reported. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 requires confirmed de novo observations with maternity and paternity confirmed. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing findings, the rule for PS3 (Moderate) is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect ... Phosphatase activity ≤ -1.11 per Mighell et al. 2018; Score -3.0814 < -1.11." The evidence for this variant shows functional assays in yeast and mouse embryonic fibroblasts demonstrate loss of PTEN phosphatase activity and inability to regulate the PI3K/AKT pathway. Therefore, PS3 is applied at Moderate strength because the functional score meets the PTEN-specific threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 requires increased prevalence in affected individuals or a proband specificity score ≥4. No case-level or case-control data are available. Therefore, PS4 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 (residues 90-94, 123-130, 166-168)." This variant occurs at residue 76, outside these domains. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Absent in population Databases present at <0.00001 allele frequency in gnomAD." The evidence shows the variant is not observed in gnomAD or other large population databases. Therefore, PM2 is applied at Supporting strength because it is absent from control populations.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 applies to recessive disorders with variants in trans. PTEN-associated disorders are dominant and no trans observations are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 applies to in-frame insertions/deletions or stop-loss variants. This is a frameshift leading to a premature stop; PM4 is not applicable. Therefore, PM4 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." This variant is a nonsense change, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 applies to assumed de novo events without confirmation. No presumed de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 relates to co-segregation with disease in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP2 applies to missense variants. This is a truncating variant; PP2 is not applicable. Therefore, PP2 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." Computational splicing analysis shows minimal impact (SpliceAI 0.03) and no missense prediction applies. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires phenotype specificity for the gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic but the evidence is not available to the laboratory to perform an independent evaluation." The variant is reported as Pathogenic in ClinVar by multiple clinical laboratories. Therefore, PP5 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." The variant is absent from gnomAD. Therefore, BA1 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." The variant is absent from population databases. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 applies to homozygous observations in unaffected individuals. No such observations exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 requires functional studies showing no damaging effect. Functional studies for this variant demonstrate damaging loss of function. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 applies to lack of segregation in multiple families. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where truncating variants are known mechanisms. This is a truncating variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 applies to observations in trans with another pathogenic PTEN variant. No such data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame repeats in non-coding regions. This variant is nonsense. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting computational evidence suggests no impact on gene or gene product." This is a truncating variant with established loss of function; computational splicing predictions do not override. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 applies when an alternate molecular basis explains the disease. No alternate diagnosis is provided. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to reputable source reports of benign impact without available evidence. ClinVar reports for this variant are pathogenic; BP6 is not applicable. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 applies to synonymous or intronic variants at specific positions. This variant is a coding nonsense change. Therefore, BP7 is not applied.