PTEN c.981del, p.Ala328GlnfsTer16
NM_000314.8:c.981del
COSMIC ID: COSM921155
Pathogenic
This frameshift variant c.981delA (A328Qfs*16) leads to a truncated PTEN protein and loss of function, is absent from population databases, and functional studies demonstrate damaging effect. It is classified as Pathogenic based on PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting).
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.981del
Protein Change
A328Qfs*16
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 328 in gene PTEN
Alternate Identifiers
COSM921155
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.981del
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
No evidence of other pathogenic variants at position 328 in gene PTEN
Functional Summary
The PTEN A328Qfs*16 variant is a truncating mutation that results in the production of C-terminally truncated PTEN proteins. Functional studies indicate that such truncating mutations lead to a loss of PTEN phosphatase function, impairing its ability to negatively regulate the PI3K/AKT pathway. Additionally, expression of PTEN truncation mutations in mouse embryonic fibroblasts has been shown to be oncogenic, increasing genome fragility due to the inability of PTEN to associate with chromosomal centromeres. This evidence supports a damaging effect of the PTEN A328Qfs*16 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 truncating frameshift c.981delA (A328Qfs*16) not in the last exon predicted to undergo nonsense-mediated decay leading to loss of function in PTEN. Therefore, this criterion is applied at Very Strong strength because the variant results in a null allele in a gene where loss of function is a known disease mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG 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: it is a frameshift, not a previously observed amino acid substitution. Therefore, this criterion is not applied because there is no matching established pathogenic change at this codon.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied due to lack of confirmed de novo evidence.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 is: "Strong Strength: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Modification Type: Disease-specific". According to PTEN pre-processing, the finding for PS3 is: the A328Qfs*16 truncating mutation abolishes PTEN phosphatase activity and is oncogenic in mouse embryonic fibroblasts, increasing genome fragility. Therefore, this criterion is applied at Strong strength because well-established functional studies demonstrate a damaging effect on PTEN.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4–15.5 OR prevalence significantly increased in affected individuals compared with controls. Modification Type: Strength". The evidence for this variant shows: no case-control or proband specificity score data are available. Therefore, this criterion is not applied due to absence of statistical or proband frequency data.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate Strength: 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: A328 is outside defined critical catalytic motifs. Therefore, this criterion is not applied because the variant does not lie within a recognized PTEN functional domain hotspot.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: 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 present in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population cohorts.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: PTEN disorders are haploinsufficient and no trans observation data apply. Therefore, this criterion is not applied as it is not relevant for a dominant LOF gene.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Protein length changes due to in-frame indels in non-repeat regions or stop-loss variants." The evidence for this variant shows: it is a frameshift causing early truncation, 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 is: "Moderate Strength: Missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before." The evidence for this variant shows: it is a frameshift, not a missense change at a previously mutated residue. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate Strength: Assumed de novo without confirmation of paternity and maternity." The evidence for this variant shows: no de novo assumption data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Co-segregation with disease in multiple affected family members with 3–4 meioses observed." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied due to lack of family studies.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Missense variant in a gene with low rate of benign missense variation where missense is common mechanism." The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect (REVEL >0.7 or splice concordance)." The evidence for this variant shows: it is a clear LOF frameshift and computational tools for splicing are not relevant. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Patient’s phenotype or family history is highly specific for a disease with a single genetic cause." The evidence for this variant shows: no detailed patient phenotype is provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source reports variant as pathogenic without accessible evidence." The evidence for this variant shows: no such external assertion is available. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: gnomAD filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: 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 Strength: allele frequency 0.0043%–0.056%." The evidence for this variant shows: allele frequency is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Observed homozygous in 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 is: "Strong Strength: Well-established functional studies show no damaging effect." The evidence for this variant shows: functional data 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 Strength: Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation studies. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense in a gene where only LOF causes disease." The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Observed in trans with pathogenic variant in recessive gene or multiple cis observations." The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame indel in repetitive region without known function." The evidence for this variant shows: it is a frameshift, not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact." The evidence for this variant shows: LOF frameshift not amenable to benign computational prediction. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting Strength: Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular diagnosis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign without evidence." The evidence for this variant shows: no such benign assertion is available. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous or intronic variant with no predicted splicing impact." The evidence for this variant shows: it is a frameshift, not synonymous or intronic. Therefore, this criterion is not applied.