Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.7 | RefSeq Select | 8514 nt | 845–2056 |
| NM_000314.5 | Alternative | 8719 nt | 1032–2243 |
| NM_000314.4 | Alternative | 5572 nt | 1032–2243 |
| NM_000314.3 | Alternative | 3416 nt | 1032–2243 |
| NM_000314.6 | Alternative | 8718 nt | 1032–2243 |
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe p.D24N pathogenic mutation (also known as c.70G>A), located in coding exon 1 of the PTEN gene, results from a G to A substitution at nucleotide position 70. The aspartic acid at codon 24 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in individuals with features consistent with PTEN hamartoma tumor syndrome in at least one individual, it was determined to be de novo (external communication). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally deficient (Mighell TL et al. Am J Hum Genet, 2018 May;102:943-955).This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 24 of the PTEN protein (p.Asp24Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of PTEN-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 185200). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTEN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect PTEN function (PMID: 17213812). This variant disrupts the p.Asp24 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24778394, 29706633; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN D24N variant, located in the phosphatase domain, has been functionally characterized as inactivating. Although it retains phosphatase activity, it exhibits aberrant nuclear localization and fails to inhibit Akt phosphorylation, cell proliferation, and transformation in cell culture, indicating a loss of function.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.02 | -85 bp |
| Donor Loss (DL) | 0.0 | 85 bp |
| Acceptor Gain (AG) | 0.0 | -270 bp |
| Donor Gain (DG) | 0.01 | 9 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: the variant is a missense change (p.D24N) and not a null variant. Therefore, this criterion is not applied because PVS1 applies only to null variants assessed via the PTEN PVS1 decision tree.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: 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. Modification Type: Disease-specific". The evidence for this variant shows: no previously established pathogenic variant results in p.D24N. Therefore, this criterion is not applied because no matching known pathogenic amino acid change exists.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Strong Strength: De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history. Modification Type: None". The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied because de novo evidence is not provided.
PS3 (Moderate)
According to PTEN Pre-processing, the finding for PS3 is: "Moderate Strength: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Phosphatase activity ≤ -1.11 per Mighell et al. 2018, PMID: 29706350. Modification Type: Disease-specific". The evidence for this variant shows: functional score -1.5498 < -1.11, with aberrant nuclear localization and failure to inhibit Akt phosphorylation consistent with loss of function. Therefore, this criterion is applied at Moderate strength because the PTEN-specific functional threshold is met.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Probands with specificity score 4-15.5 OR The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls. Modification Type: Strength". The evidence for this variant shows: no case-level or prevalence data are available. Therefore, this criterion is not applied because case-level evidence is lacking.
PM1 (Not Applied)
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. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3). Modification Type: Disease-specific". The evidence for this variant shows: residue D24 lies outside these defined catalytic motifs. Therefore, this criterion is not applied because the variant is not in a mutational hot spot or critical domain.
PM2 (Supporting)
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. Modification Type: Disease-specific". The evidence for this variant shows: absent from gnomAD (MAF 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3 (Not Applied)
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 evidence of occurrence in trans with another PTEN pathogenic variant. Therefore, this criterion is not applied because PM3 is not met.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Moderate Strength: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Applies to in-frame insertions or deletions impacting at least one residue in a catalytic motif. Modification Type: Disease-specific". The evidence for this variant shows: missense substitution with no protein length change. Therefore, this criterion is not applied because PM4 applies to in-frame indels or protein length changes.
PM5 (Not Applied)
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. Modification Type: Disease-specific". The evidence for this variant shows: no other known pathogenic missense at residue D24. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Strong Strength: Two probands with presumed de novo occurrence or as specified. Modification Type: Strength". The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied because de novo evidence is not provided.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed. Modification Type: Disease-specific". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied because segregation evidence is missing.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting Strength: Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: insufficient data to conclude PTEN has a low rate of benign missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Missense variants: REVEL score > 0.7. Modification Type: Disease-specific". The evidence for this variant shows: mixed computational predictions with overall benign lean. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Supporting Strength: Phenotype specificity for gene with single genetic etiology." The evidence for this variant shows: no patient phenotype data provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Strength: Reputable source recently reports variant as pathogenic, but the evidence is not available to perform an independent evaluation." The evidence for this variant shows: ClinVar reports the variant as Pathogenic by three clinical laboratories. Therefore, this criterion is applied at Supporting strength.
BA1 (Not Applied)
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: MAF = 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%). Modification Type: Disease-specific". The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Observed in the homozygous state in a healthy or PHTS-unaffected individual. Modification Type: Disease-specific". The evidence for this variant shows: no homozygous observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong Strength: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function. Modification Type: Disease-specific". The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Lack of segregation in affected members of two or more families. Modification Type: Disease-specific". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Strength: Missense variant in a gene where only truncation causes disease." The evidence for this variant shows: missense variants in PTEN can be pathogenic. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting Strength: Observed in trans with a pathogenic PTEN variant." The evidence for this variant shows: no observations in trans with another PTEN variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting Strength: In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: missense substitution. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Multiple lines of computational evidence suggest no impact on gene or gene product. Missense variants: REVEL scores < 0.5. Modification Type: Disease-specific". The evidence for this variant shows: mixed in silico predictions with overall benign lean and SpliceAI score 0.02 (no splicing impact). Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
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. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting Strength: Reputable source reports variant as benign, but evidence is not available." The evidence for this variant shows: no reputable benign report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: A synonymous (silent) or intronic variant at or beyond +7/-21 with no predicted splicing impact." The evidence for this variant shows: missense substitution. Therefore, this criterion is not applied.