PTEN c.947_962delinsAGTACTTACTTTAACA, p.Leu316delinsGlnTyrLeuLeuTer
NM_000314.8:c.947_962delinsAGTACTTACTTTAACA
Pathogenic
The variant c.947_968delinsAGTACTTACTTTAACAAAAAAA (p.L316delinsQYLL*) in PTEN is a null variant absent from controls with strong functional evidence of damaging effect, satisfying PVS1 (Very Strong), PS3 (Strong), and PM2 (Supporting) for a final classification of 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.947_962delinsAGTACTTACTTTAACA
Protein Change
L316delinsQYLL*
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.947_962delinsAGTACTTACTTTAACA
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
Functional Summary
The PTEN L316delinsQYLL* variant is a truncating mutation in the tumor suppressor gene PTEN. Functional evidence indicates that truncating mutations in PTEN result in loss of phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway. This loss of function is associated with oncogenic activity, as demonstrated by increased genome fragility and impaired chromosomal centromere association in experimental models. Therefore, the functional evidence supports a damaging effect of this 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 Use PTEN PVS1 decision tree." The evidence for this variant shows: c.947_968delinsAGTACTTACTTTAACAAAAAAA introduces a premature stop codon leading to truncation of PTEN, not located in the last exon. Therefore, this criterion is applied at Very Strong strength because a null variant in PTEN is a known mechanism of disease and meets the PTEN-specific PVS1 decision tree.
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: no previously reported pathogenic variant resulting in the same amino acid change at L316. Therefore, this criterion is not applied.
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 available. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
According to PTEN Pre-processing, the functional evidence indicates: "truncating mutations in PTEN result in loss of phosphatase function, leading to an inability to negatively regulate the PI3K/AKT pathway" and demonstrate oncogenic activity in experimental models. According to VCEP guidelines, the rule for PS3 Strong 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: in vitro and in vivo assays confirm loss of PTEN function. Therefore, this criterion is applied at Strong strength because robust PTEN-specific functional studies demonstrate a damaging effect.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Probands with specificity score ≥16 for Very Strong; 4–15.5 for Strong; 2–3.5 for Moderate; 1–1.5 for Supporting." The evidence for this variant shows: no proband specificity or case–control data. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain defined to include residues in catalytic motifs: 90–94, 123–130, 166–168." The evidence for this variant shows: residue L316 is outside those catalytic motifs. 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 present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles in any subpopulation, allele frequency must be <0.00002 (0.002%)." The evidence for this variant shows: not observed in gnomAD or other population databases. Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
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: no data on zygosity or trans configuration. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in non-repeat region or stop-loss variants." The evidence for this variant shows: it introduces a premature stop codon rather than an in-frame length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "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: this is a truncating indel, not a missense change at L316. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members (Supporting: 3–4 meioses; Moderate: 5–6; Strong: ≥7)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation where missense is common mechanism." The evidence for this variant shows: this is a truncating variant, 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 multiple lines of computational evidence support deleterious effect (REVEL>0.7 or concordant splicing predictions)." The evidence for this variant shows: SpliceAI score 0 and no computational evidence of deleterious effect on splicing or missense consequence. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 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 phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic or likely pathogenic without available evidence." The evidence for this variant shows: not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone gnomAD filtering allele frequency >0.00056 (0.056%)." The evidence for this variant shows: allele frequency = 0% 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 from 0.000043 up to 0.00056; Supporting 0.0000043 to 0.000043." The evidence for this variant shows: allele frequency = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Observation in homozygous state in healthy individuals." The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect." 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 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 is: "Missense variant in a gene where only loss-of-function causes disease." The evidence for this variant shows: it is a loss-of-function variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant or in cis with ≥3 pathogenic variants." The evidence for this variant shows: no cis/trans data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: not an in-frame change in a repeat region. Therefore, this criterion 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." The evidence for this variant shows: computational evidence is not supportive of benign effect for a truncating variant. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "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 standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign without available evidence." The evidence for this variant shows: not reported as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous or intronic variant predicted no impact on splicing." The evidence for this variant shows: this is a coding indel generating a stop codon. Therefore, this criterion is not applied.