PTEN c.77C>T, p.Thr26Ile
NM_000314.8:c.77C>T
COSMIC ID: COSM6936497
Likely Pathogenic
This PTEN missense variant (T26I) has only one supporting criterion (PP3) based on a high REVEL score. All other evidence criteria are unfulfilled or not applicable. Consequently, the variant is classified as a Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PP3
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.77C>T
Protein Change
T26I
Location
Exon 1
(Exon 1 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 26: T26P
Alternate Identifiers
COSM6936497
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.77C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00318%
Rare
Highest in Population
European (non-Finnish)
0.00648%
Rare
Global: 0.00318%
European (non-Finnish): 0.00648%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 31410Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00318%, 1/31410 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00648%, 1/15434 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
2 publications
Likely Pathogenic
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
2 Path
1 LP
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (2)
The 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.
Clinical Statement
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).
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
ClinVar reports other pathogenic variants at position 26: T26P
PM5 criterion applied.
Functional Summary
The PTEN T26I variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.953
0.953
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
metasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 5.27polyphen_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. 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
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...'. 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
PS2 (Not Applied) Strength Modified
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
PS3 (Not Applied) Strength Modified
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
PS4 (Not Applied) Strength Modified
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
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 (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
PM2 (Not Applied) 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'. 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
PM3 (Not Applied) Strength Modified
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
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 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
PM5 (Not Applied) Strength Modified
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
PM6 (Not Applied) Strength Modified
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
PP1 (Not Applied) Strength Modified
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
PP2 (Not Applied) Strength Modified
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
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
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 data. Therefore, this criterion is not applied.
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 MAF = 0.0000318. Therefore, this criterion is not applied because the allele frequency is below the BA1 threshold.
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 MAF = 0.0000318, which is below the lower bound. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
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
BS3 (Not Applied) Strength Modified
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
BS4 (Not Applied) Strength Modified
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
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 cause disease'. The evidence for this variant shows PTEN has known pathogenic missense variants. 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 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
BP3 (Not Applied) Strength Modified
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
BP4 (Not Applied) Strength Modified
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
BP5 (Not Applied) Strength Modified
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
BP6 (Not Applied) Strength Modified
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
BP7 (Not Applied) Strength Modified
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.