PTEN c.828T>A, p.Asn276Lys
NM_000314.8:c.828T>A
COSMIC ID: COSM6506719
Likely Pathogenic
NM_000314.8:c.828T>A (p.N276K) in PTEN is classified as Likely Pathogenic based on Moderate functional evidence (PS3_Moderate), Moderate evidence from prior pathogenic missense at the same residue (PM5_Moderate), supporting absence in population databases (PM2_Supporting), and supporting computational predictions (PP3_Supporting).
ACMG/AMP Criteria Applied
PS3
PM2
PM5
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.828T>A
Protein Change
N276K
Location
Exon 8
(Exon 8 of 9)
5'Exon Structure (9 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 276: N276D, N276S, N276I
Alternate Identifiers
COSM6506719
Variant interpretation based on transcript NM_000314.8
Genome Browser
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HGVS InputNM_000314:c.828T>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
Uncertain Significance (VUS)
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (1 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 276: N276D, N276S, N276I
PM5 criterion applied.
Functional Summary
The PTEN N276K variant has been functionally characterized and is associated with reduced phosphatase activity, as demonstrated in a yeast assay. This reduction in activity suggests a likely loss of PTEN protein function.
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
0.798
0.798
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:
polyphen_prediction: probably_damagingmutationtaster: Dmetasvm: Dmetalr: Dprimateai: D
Benign:
CADD: 4.30
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: N276K is a missense change, not a null variant predicted to result in loss-of-function. Therefore, this criterion is not applied because the variant does not meet the null variant requirement.
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.' The evidence for this variant shows: there is no prior report of the same p.N276K change as pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Very Strong: Two proven OR four assumed OR one proven + two assumed de novo observations in a patient with the disease and no family history.' The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to PTEN Pre-processing, the finding for PS3 is: 'Phosphatase activity score -3.9178 < -1.11 per Mighell et al. 2018, meeting threshold for PS3_Moderate.' The evidence for this variant shows: yeast assay demonstrates reduced PTEN phosphatase activity with a score of -3.9178. Therefore, this criterion is applied at Moderate strength because the functional score meets the VCEP 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 cases vs controls.' The evidence for this variant shows: no proband phenotype data or case counts are provided. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: 'Moderate: Located in catalytic motifs residues 90–94, 123–130, or 166–168.' The evidence for this variant shows: p.N276K lies outside these catalytic motif regions. 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 <0.001% allele frequency in gnomAD.' The evidence for this variant shows: not observed in gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: 'Moderate: Detected in trans with a pathogenic variant in an autosomal recessive gene.' The evidence for this variant shows: PTEN-related conditions are autosomal dominant and no trans observations are reported. 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 indels or stop-loss variants.' The evidence for this variant shows: p.N276K is a missense change, not an in-frame indel or stop-loss. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
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, with BLOSUM62 score equal or less.' The evidence for this variant shows: a different pathogenic missense at residue 276 has been reported. Therefore, this criterion is applied at Moderate strength because the residue has prior pathogenic missense variation.
PM6
PM6 (Not Applied) Strength Modified
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 information is available. 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 (3–4 meioses).' The evidence for this variant shows: no segregation data are provided. 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 mechanism.' The evidence for this variant shows: although PTEN missense variants cause disease, specific gene constraint metrics are not provided. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, the rule for PP3 is: 'Supporting: Multiple lines of computational evidence support a deleterious effect; for missense variants REVEL > 0.7.' The evidence for this variant shows: REVEL score = 0.80 (>0.7) and other tools predict damaging. Therefore, this criterion is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Supporting: Patient’s phenotype or family history highly specific for a single genetic etiology.' The evidence for this variant shows: no clinical phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Supporting: Reputable source reports the variant as pathogenic without available evidence.' The evidence for this variant shows: ClinVar reports it as VUS, not pathogenic. 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 >0.056%.' The evidence for this variant shows: not observed in population (MAF=0%). Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: 'Strong: gnomAD allele frequency 0.0043%–0.056%.' The evidence for this variant shows: MAF=0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: 'Strong: Observed homozygous in a healthy or PHTS-unaffected individual.' The evidence for this variant shows: no homozygous observations reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: 'Supporting: Phosphatase activity >0 per Mighell et al. 2018 showing no damaging effect.' The evidence for this variant shows: activity is significantly reduced (<0). Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: 'Supporting: Lack of segregation in affected members of one family.' 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 gene where only truncating variants cause disease.' The evidence for this variant shows: PTEN disease mechanism includes 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.' 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 indels in repetitive region.' The evidence for this variant shows: p.N276K is a missense substitution. 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; for missense REVEL <0.5.' The evidence for this variant shows: REVEL = 0.80 (>0.5). Therefore, this criterion is not applied.
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 diagnosis. 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 without evidence.' The evidence for this variant shows: no such reports. 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 with no splicing impact.' The evidence for this variant shows: p.N276K is missense. Therefore, this criterion is not applied.