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
Open"This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratories) and as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN A121T variant has not been functionally characterized, and its effect on PTEN protein function remains unknown.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -125 bp |
| Donor Loss (DL) | 0.0 | 9 bp |
| Acceptor Gain (AG) | 0.0 | 375 bp |
| Donor Gain (DG) | 0.0 | 131 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." The evidence for this variant shows that it is a missense change (A121T) and not a null variant. Therefore, this criterion is not applied because the variant type does not meet PVS1 (null variant) requirements.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change..." The evidence for this variant shows no other nucleotide change resulting in A121T has been established as pathogenic. Therefore, this criterion is not applied due to lack of an identical amino acid change previously classified as pathogenic.
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 occurrence data. Therefore, this criterion is not applied because there is no de novo evidence.
PS3 (Not Applied)
According to PTEN Pre-processing, the finding for PS3 is: "Score (-0.3725) did not meet threshold (-1.11) for PS3_Moderate." The evidence for this variant shows a phosphatase activity score of -0.3725. Therefore, this criterion is not applied at Moderate strength because the functional assay result did not meet the VCEP threshold for damaging effect.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong: Probands with specificity score 4-15.5 OR prevalence significantly increased in affected vs controls..." The evidence for this variant shows no case or cohort data. Therefore, this criterion is not applied due to absence of proband frequency data.
PM1 (Not Applied)
According to VCEP guidelines, the rule for PM1 is: "Moderate: Located in a mutational hot spot and/or critical and well-established functional domain... residues in catalytic motifs: 90-94, 123-130, 166-168." The evidence for this variant shows residue A121 is outside the specified motifs. Therefore, this criterion is not applied because the variant is not in a defined hotspot or critical domain.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent in population Databases present at <0.00001 allele frequency in gnomAD..." The evidence for this variant shows it is absent from gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is not observed in large population datasets.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Moderate: For recessive disorders, detected in trans with a pathogenic variant..." The evidence for this variant shows no data on trans observations in a recessive context. Therefore, this criterion is not applied due to lack of recessive inheritance evidence.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: "Moderate: Protein length changes due to in-frame deletions/insertions..." The evidence for this variant shows a missense change rather than an in-frame indel. Therefore, this criterion is not applied because it does not alter protein length.
PM5 (Moderate)
According to VCEP guidelines, the rule for PM5 is: "Moderate: Missense change at an amino acid residue where a different missense change determined to be pathogenic or likely pathogenic has been seen before..." The evidence for this variant shows that another missense at residue A121 has been reported as pathogenic and BLOSUM62 score criteria are met. Therefore, this criterion is applied at Moderate strength because of the presence of a different known pathogenic missense at the same residue.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: "Moderate: Assumed de novo without confirmation of paternity and maternity..." The evidence for this variant shows no de novo assumptions. Therefore, this criterion is not applied due to lack of de novo data.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting: Co-segregation with disease in multiple affected family members, ≥3–4 meioses..." The evidence for this variant shows no segregation data. Therefore, this criterion is not applied because family co-segregation is not available.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant and gene do not clearly meet these requirements per VCEP specifications. Therefore, this criterion is not applied.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: "Supporting: Multiple lines of computational evidence support a deleterious effect... REVEL score > 0.7." The evidence for this variant shows a REVEL score of 0.82 (>0.7). Therefore, this criterion is applied at Supporting strength because computational predictions support a deleterious impact.
PP4 (Not Applied)
According to VCEP guidelines, the rule for PP4 is: "Supporting: Phenotype specificity for disease with single genetic etiology..." The evidence for this variant shows no specific patient phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic, but evidence not available for independent evaluation." The evidence shows conflicting ClinVar submissions (Likely pathogenic and Uncertain). Given VCEP emphasis on independent evaluation, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: gnomAD Filtering allele frequency >0.00056 (0.056%)." The evidence shows allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong: Allele frequency from 0.000043 up to 0.00056." The evidence shows allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong: Observed in homozygous state in healthy individuals..." The evidence shows no homozygous observations. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established functional studies show no damaging effect..." The evidence shows no such studies for this variant. 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 shows no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Supporting: Missense variant in gene where only truncating variants cause disease." PTEN disease mechanism includes missense. 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..." The evidence shows no phasing data. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame indels in repetitive region without a known function." The evidence shows 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... REVEL score < 0.5." The evidence shows REVEL 0.82 (>0.5). Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP guidelines, the rule for BP5 is: "Supporting: Variant found in case with alternate molecular basis..." The evidence shows no alternate molecular basis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source reports variant as benign, but evidence not available." No such benign reports exist. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting: Synonymous or intronic variant with no predicted splicing impact..." The evidence shows a missense change. Therefore, this criterion is not applied.