PTEN c.70G>A, p.Asp24Asn
NM_000314.8:c.70G>A
COSMIC ID: COSM5079
Likely Pathogenic
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
PS3
PM2
PP2
PP5
BP4
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.70G>A
Protein Change
D24N
Location
Exon 1
(Exon 1 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 24 in gene PTEN
Alternate Identifiers
COSM5079
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.70G>A
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
2 publications
Pathogenic
Based on 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The 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.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 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 24 in gene PTEN
Functional Summary
The PTEN D24N variant, located in the phosphatase domain, retains phosphatase activity but exhibits aberrant nuclear localization. It fails to inhibit Akt phosphorylation, cell proliferation, and transformation in cell culture, indicating a loss of function. This functional evidence supports a damaging effect of the variant.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.26polyphen_prediction: benign
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Use PTEN PVS1 decision tree." The evidence for this variant shows: p.D24N is a missense change and not a null or canonical splice variant. Therefore, this criterion is not applied because the variant does not meet the PTEN PVS1 decision tree requirements.
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 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 established pathogenic variant at codon 24 producing the same amino acid change. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: "Strong 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 confirmed de novo observations reported. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: "High-confidence functional score -1.5498 < threshold -1.11 indicating phosphatase activity below threshold." The evidence for this variant shows: in vitro studies demonstrate aberrant nuclear localization and failure to inhibit Akt phosphorylation, with a phosphatase activity score of -1.5498. Therefore, this criterion is applied at Moderate strength because the functional score meets the PTEN-specific PS3 moderate threshold.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Probands with specificity score 4-15.5 or significant increase in prevalence in cases vs controls." The evidence for this variant shows: no proband counts or case-control data available. Therefore, this criterion 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 defined to include residues in catalytic motifs: 90-94, 123-130, 166-168." The evidence for this variant shows: residue D24 lies outside the defined 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..." The evidence for this variant shows: not found in gnomAD or other large population databases (MAF=0%). 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: "Moderate For recessive disorders, detected in trans with a pathogenic variant." The evidence for this variant shows: no evidence of recessive in trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM4 is: "Moderate Protein length changes due to in-frame deletions/insertions in non-repeat region..." The evidence for this variant shows: p.D24N is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate Missense change at a residue where a different missense change determined to be pathogenic has been seen before..." The evidence for this variant shows: no other pathogenic missense reported at codon 24. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 is: "Moderate Assumed de novo without confirmation of paternity/maternity in a proband with disease and no family history." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Co-segregation with disease in multiple affected family members, with 3-4 meioses observed." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Supporting)
According to VCEP guidelines, the rule for PP2 is: "Supporting 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: PTEN has a low rate of benign missense and missense is a common disease mechanism. Therefore, this criterion is applied at Supporting strength.
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 (REVEL > 0.7 for missense)." The evidence for this variant shows: mixed in silico predictions with REVEL not consistently >0.7 and SpliceAI indicating no splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Supporting 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/family history data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting Reputable source recently reports variant as pathogenic but evidence unavailable for independent evaluation." The evidence for this variant shows: ClinVar lists this variant as Pathogenic by three clinical laboratories. Therefore, this criterion 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 (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 gnomAD Filtering allele frequency from 0.000043 up to 0.00056." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Observed in homozygous state in healthy or PHTS-unaffected individual." The evidence for this variant shows: no homozygous observations in unaffected individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong Well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effects. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Lack of segregation in affected members of two or more families." The evidence for this variant shows: no segregation evidence. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Supporting Missense variant in a gene for which primarily truncating variants are known to cause disease." The evidence for this variant shows: PTEN disease mechanism includes missense. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP2 is: "Supporting Observed in trans with a pathogenic or likely pathogenic PTEN variant OR ≥3 observations in cis/phase unknown." 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 In-frame deletions/insertions in repetitive region without a known function." The evidence for this variant shows: p.D24N is missense, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Multiple lines of computational evidence suggest no impact on gene or gene product; for missense, REVEL < 0.5." The evidence for this variant shows: mixed computational predictions leaning benign and SpliceAI score 0.02 indicating no splice impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Supporting 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: "Supporting Reputable source reports variant as benign but evidence not available." The evidence for this variant shows: no reputable benign classification reported. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting Synonymous or intronic variant beyond consensus splice sites with no predicted splice impact." The evidence for this variant shows: p.D24N is missense, not synonymous. Therefore, this criterion is not applied.