PTEN c.991_992del, p.Asp331GlnfsTer11
NM_000314.8:c.991_992del
Pathogenic
The PTEN c.991_992del (p.Asp331Glnfs*11) variant is a truncating frameshift outside the last exon, absent from population databases, reported pathogenic in ClinVar, and functionally damaging in established assays. PVS1_VeryStrong plus PS3_Strong, together with PM2_Supporting and PP5_Supporting, meet ACMG criteria for a final classification of Pathogenic.
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.991_992del
Protein Change
D331Qfs*11
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 331 in gene PTEN
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.991_992del
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
1 publications
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This sequence change results in a premature translational stop signal in the PTEN gene (p.Asp331Glnfs*11). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acids of the PTEN protein. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTEN-related disease. This variant is expected to result in the disruption of the last 73 amino acid residues (Asp331-Val403) of the PTEN protein. This removes the C-terminal portion of the C2 domain, as well as the entire C-tail domain and PDZ binding domain (PMID: 25448482, 25336918, 24905788). This variant also deletes several critical phosphorylation sites within the C-tail domain, which are important for regulating PTEN protein stability and function (PMID: 12297295, 10866658, 11035045, 10468583). For these reasons, this variant has been classified as Pathogenic. No functional studies have been performed to test the effects of this variant on PTEN protein stability, cellular location, or function. However, experimental studies have shown that other C-terminal truncating variants in this region affect the stability and function of the PTEN protein (PMID: 10468583, 10698513, 24905788). This suggests that disruption of this region of the PTEN protein is causative of disease.
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 331 in gene PTEN
Functional Summary
The PTEN D331Qfs*11 variant is a truncating mutation that results in a 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, as they increase genomic fragility and disrupt PTEN's association with chromosomal centromeres. Therefore, this variant is functionally characterized as damaging.
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." The evidence for this variant shows it is a truncating frameshift (c.991_992del, p.Asp331Glnfs*11) in a gene where loss of function is a known disease mechanism and is not located in the last exon. Therefore, this criterion is applied at Very Strong strength because the PTEN PVS1 decision tree specifies that such truncating variants outside the last exon qualify for PVS1_VeryStrong.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 requires the same amino acid change as a known pathogenic variant. This variant results in a frameshift, not the same amino acid change as any known pathogenic variant. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires de novo occurrence with confirmed maternity and paternity. No parental testing or de novo information is provided. Therefore, PS2 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." The PTEN pre-processing result found functional studies demonstrating that the D331Qfs*11 truncating variant abolishes phosphatase activity and is oncogenic. Therefore, PS3 is applied at Strong strength because well-established functional assays show damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals or specificity score ≥4. No case-control or proband prevalence data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants in defined catalytic motifs (residues 90-94, 123-130, 166-168). The variant occurs at residue 331, outside these motifs. Therefore, PM1 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 allele frequency in gnomAD or another large sequenced population." The variant is not found in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because it is absent from large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM3 applies to variants observed in trans with another pathogenic variant in a recessive disorder. PTEN disorders are autosomal dominant and no trans observations are provided. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, PM4 applies to in-frame indels or protein extensions. This variant is a frameshift leading to premature stop, not an in-frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to different missense changes at the same residue as known pathogenic missense variants. This is a frameshift, not a missense change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo occurrences without confirmation. No de novo information is provided. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation in multiple affected family members. No segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation. This variant is a frameshift, not missense. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 requires multiple lines of computational evidence supporting deleterious effect. SpliceAI score is 0.02 and there are no in silico predictions for missense impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a highly specific phenotype with a single genetic etiology. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: "Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation." ClinVar lists this variant as Pathogenic by one clinical laboratory. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies at >0.056% allele frequency. The variant is absent in population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies at allele frequency ≥0.0043% but <0.056%. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, 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, BS3 requires functional studies showing no damaging effect. Functional studies show damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected members. No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 applies to missense variants in genes where only truncating variants cause disease. This is a truncating variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, BP2 applies to trans occurrences with pathogenic variants. No such observations. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a frameshift, not in-frame. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 requires multiple lines of computational evidence for no impact. The variant is frameshift LOF. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when an alternate molecular basis exists. No alternate basis is described. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to a reputable source reporting a benign outcome. No benign reports exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This is a frameshift. Therefore, BP7 is not applied.