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 c.77C>T (p.T26I) alteration is located in exon 1 (coding exon 1) of the PTEN gene. This alteration results from a C to T substitution at nucleotide position 77, causing the threonine (T) at amino acid position 26 to be replaced by an isoleucine (I). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (1/31410) total alleles studied. The highest observed frequency was 0.006% (1/15434) of European (non-Finnish) alleles. This alteration has been identified as a de novo variant in patients meeting criteria for PTEN hamartoma tumor syndrome, however paternity was not confirmed in either case (Busa, 2015; external communication). Another alteration at the same codon, c.76A>C (p.T26P), has been detected in several patients who reportedly met clinical diagnostic criteria for Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome, or relaxed clinical diagnostic criteria for CS-like, however precise clinical features were not provided (Sarquis, 2006; Pilarski, 2011; Tan, 2011; Nizialek, 2015). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). In a massively parallel functional assay using a humanized yeast model, lipid phosphatase activity for this variant was functionally neutral (Mighell, 2018). In another study, this alteration demonstrated partial PIP3 phosphatase activity and abnormal subcellular localization (Mingo, 2018). Based on the available evidence, this alteration is classified as likely pathogenic.
This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 26 of the PTEN protein (p.Thr26Ile). This variant is present in population databases (rs786204853, gnomAD 0.007%). This missense change has been observed in individual(s) with PTEN-related conditions (PMID: 25549896). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 189399). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects PTEN function (PMID: 29706633). This variant disrupts the p.Thr26 amino acid residue in PTEN. Other variant(s) that disrupt this residue have been observed in individuals with PTEN-related conditions (PMID: 22595938; internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
"This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratories) and as Likely pathogenic (1 clinical laboratories) and as Pathogenic (2 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
The PTEN T26I variant has not been functionally characterized, and its biological significance remains unknown.
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -92 bp |
| Donor Loss (DL) | 0.03 | 91 bp |
| Acceptor Gain (AG) | 0.0 | -296 bp |
| Donor Gain (DG) | 0.03 | 2 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 (T26I) and does not lead to a null transcript. Therefore, this criterion is not applied because missense variants do not meet PVS1 under the PTEN decision tree.
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 pathogenic missense change at residue 26. Therefore, this criterion is not applied because there is no previously established pathogenic variant causing T26I by a different nucleotide change.
PS2 (Not Applied)
According to VCEP guidelines, the rule for PS2 is: 'Strong De novo (both maternity and paternity confirmed)...' or 'Very Strong Two proven OR four assumed OR one proven + two assumed de novo observations...'. The evidence for this variant shows no de novo data. Therefore, this criterion is not applied due to lack of de novo occurrence evidence.
PS3 (Not Applied)
According to PTEN Pre-processing, the finding for PS3_Moderate is: 'Score (-0.6874) did not meet threshold (-1.11) for PS3_Moderate'. The evidence for this variant shows a phosphatase activity score of -0.6874. Therefore, this criterion is not applied because the variant did not meet the PTEN-specific functional threshold.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Strong Probands with specificity score 4-15.5 OR increased prevalence in affected vs. controls'. The evidence for this variant shows no data on affected probands or prevalence comparisons. Therefore, this criterion is not applied due to absence of case 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 90-94, 123-130, 166-168)'. The evidence for this variant shows position 26 is outside these domains. Therefore, this criterion is not applied because the residue is not in a defined hotspot or functional domain.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 is: 'Supporting Absent in population databases present at <0.00001 (0.001%) allele frequency in gnomAD'. The evidence for this variant shows MAF = 0.00318% (0.0000318), which exceeds the threshold. Therefore, this criterion is not applied because the allele frequency is above the VCEP cutoff for rarity.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Supporting Observed in trans with a pathogenic PTEN variant OR at least three observations in cis...'. The evidence for this variant shows no data on allelic phase with other PTEN variants. Therefore, this criterion is not applied due to lack of trans/cis observation data.
PM4 (Not Applied)
According to VCEP guidelines, the rule for PM4 is: 'Moderate Protein length changes due to in-frame deletions/insertions in a non-repeat region...'. The evidence for this variant shows a missense substitution with no protein length change. Therefore, this criterion is not applied.
PM5 (Not Applied)
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 no other pathogenic missense at residue 26. Therefore, this criterion is not applied due to absence of a different known pathogenic change at the same residue.
PM6 (Not Applied)
According to VCEP guidelines, the rule for PM6 is: 'Strong Two probands with presumed de novo occurrence OR Very Strong two proven de novo...'. The evidence for this variant shows no presumed de novo occurrences. 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...'. The evidence for this variant shows no segregation data. Therefore, this criterion is not applied.
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 is a common disease mechanism'. The evidence for this variant shows PTEN disease mechanism is primarily loss-of-function; missense effects are variable. Therefore, this criterion is not applied due to uncertainty about missense mechanism prevalence.
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Supporting Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Missense variants: REVEL score > 0.7'. The evidence for this variant shows REVEL = 0.95. Therefore, this criterion is applied at Supporting strength because the REVEL score exceeds the VCEP threshold.
PP4 (Not Applied)
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 data. Therefore, 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 for this variant shows MAF = 0.0000318. Therefore, this criterion is not applied because the allele frequency is below the BA1 threshold.
BS1 (Not Applied)
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 MAF = 0.0000318, which is below the lower bound. 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. 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'. The evidence for this variant shows no such functional studies. 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 families'. 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 Missense variant in a gene for which primarily truncating variants cause disease'. The evidence for this variant shows PTEN has known pathogenic 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 at least three observations in cis...'. The evidence for this variant shows no observations in cis/trans with other variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to VCEP guidelines, the rule for BP3 is: 'Supporting In-frame indels in repetitive regions without a known function'. The evidence for this variant shows a missense change, not an in-frame indel. 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 < 0.5)'. The evidence for this variant shows REVEL = 0.95. Therefore, this criterion is not applied.
BP5 (Not Applied)
According to VCEP 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 findings. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Supporting Reputable source recently reports variant as benign'. The evidence for this variant shows no such benign reports. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Supporting A synonymous or intronic variant with no splicing impact'. The evidence for this variant shows a missense substitution. Therefore, this criterion is not applied.