Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000314.8 | MANE Select | 8515 nt | 846–2057 |
| 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 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenThe p.A126V variant (also known as c.377C>T), located in coding exon 5 of the PTEN gene, results from a C to T substitution at nucleotide position 377. The alanine at codon 126 is replaced by valine, an amino acid with similar properties. In a yeast-based functional assay, PIP3 phosphatase activity was measured and this alteration, which resides in the P-catalytic loop, gave rise to a fully inactive protein (Rodríguez-Escudero I et al. Hum. Mol. Genet., 2011 Nov;20:4132-42). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with PTEN Hamartoma Tumor syndrome-related disease (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
This sequence change replaces alanine with valine at codon 126 of the PTEN protein (p.Ala126Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of PTEN hamartoma tumor syndrome (PMID: 28195393; Invitae). ClinVar contains an entry for this variant (Variation ID: 428234). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTEN function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PTEN function (PMID: 21828076, 26504226, 29706350). This variant disrupts the p.Ala126 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22266152, 22595938, 29706350). 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 Likely pathogenic (2 clinical laboratories) and as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN A126V variant has been functionally characterized and shown to result in a loss of PTEN phosphatase activity. This mutation, located in the phosphatase domain, leads to decreased protein activity and loss of PI3K inhibition, indicating a damaging effect.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -141 bp |
| Donor Loss (DL) | 0.0 | 115 bp |
| Acceptor Gain (AG) | 0.0 | 65 bp |
| Donor Gain (DG) | 0.0 | -7 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Use PTEN PVS1 decision tree. Modification Type: Disease-specific". The evidence for this variant shows: it is a missense change (p.Ala126Val), not a null variant. Therefore, this criterion is not applied because the variant type does not meet PVS1 requirements.
PS1 (Not Applied)
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...". The evidence for this variant shows: no other nucleotide change yielding p.Ala126Val has been reported as pathogenic. Therefore, this criterion is not applied because no established pathogenic variant matches this amino acid change via a different nucleotide change.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: "Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations...". The evidence for this variant shows: no de novo occurrences with confirmed maternity/paternity are reported. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3 (Moderate)
According to PTEN Pre-processing, the finding for PS3 is: "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: PTEN A126V has a functional score of -1.7401 (< -1.11) and demonstrated loss of phosphatase activity. Therefore, this criterion is applied at Moderate strength because the functional score passes the disease-specific threshold.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Very Strong Probands with specificity score ≥16; Strong Probands with specificity score 4-15.5; Moderate 2-3.5; Supporting 1-1.5". The evidence for this variant shows: no case-control or proband specificity data are provided. Therefore, this criterion is not applied.
PM1 (Moderate)
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... Modification Type: Disease-specific". The evidence for this variant shows: p.Ala126Val lies within the catalytic motif 123-130 of PTEN. Therefore, this criterion is applied at Moderate strength because the variant is within a defined critical functional domain.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Absent in population Databases present at <0.00001 (0.001%) allele frequency in gnomAD... Modification Type: Disease-specific". The evidence for this variant shows: it is absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because it meets the VCEP absence threshold.
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: PTEN-associated conditions are inherited dominantly and no trans observations are reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region...". The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Moderate)
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 or likely pathogenic has been seen before... Modification Type: Disease-specific". The evidence for this variant shows: residue 126 has other pathogenic missense changes reported (e.g., p.Ala126Thr). Therefore, this criterion is applied at Moderate strength because it is a novel missense at a residue with known pathogenic variants.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity...". The evidence for this variant shows: no de novo assumptions reported. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting: co-segregation with disease in multiple affected family members...". The evidence for this variant shows: no segregation data are provided. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "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: although PTEN has pathogenic missense variants, the gene does not have exceptionally low benign variation to confidently apply PP2. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "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: REVEL score is 0.96 (>0.7) and multiple in silico tools predict damaging. Therefore, this criterion is applied at Supporting strength because computational evidence is concordant.
PP4 (Not Applied)
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 data are provided. Therefore, this criterion is not applied.
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.". The evidence for this variant shows: ClinVar has two labs reporting Likely Pathogenic and two labs reporting Pathogenic. Therefore, this criterion is applied at Supporting strength because reputable sources report pathogenicity.
BA1 (Not Applied)
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% in gnomAD. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: gnomAD Filtering allele frequency from 0.000043 to 0.00056.". The evidence for this variant shows: not present in gnomAD. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: Observed in the homozygous state in a healthy or PHTS-unaffected individual.". The evidence for this variant shows: no homozygous observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established in vitro or in vivo functional studies shows no damaging effect on protein function.". The evidence for this variant shows: functional studies demonstrate a damaging effect. Therefore, this criterion is not applied.
BS4 (Not Applied)
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 data available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "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 variants. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to VCEP guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic PTEN variant or in cis with multiple pathogenic variants.". The evidence for this variant shows: no cis or trans observations with other PTEN variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in a repetitive region without a known function.". The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.
BP4 (Not Applied)
According to VCEP guidelines, the rule for BP4 is: "Supporting: Multiple lines of computational evidence suggest no impact (Missense variants: REVEL <0.5).". The evidence for this variant shows: REVEL = 0.96, predictive of damage. Therefore, this criterion is not applied.
BP5 (Not Applied)
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 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available.". The evidence for this variant shows: no reputable source reports benign. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to standard ACMG guidelines, the rule for BP7 is: "A synonymous or intronic variant at or beyond +7/-21 with no predicted splice impact.". The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.