PVS1 (Very Strong): c.844G>T is a nonsense variant producing a premature termination codon at position 282 (p.Gly282Ter), located well 5' to the p.D375 threshold in exon 8 of the biologically-relevant transcript NM_000314.8. Per the PTEN VCEP decision tree, this is predicted to undergo NMD and is assigned PVS1 at Very Strong strength.1 PS3 (Moderate): The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay demonstrates a cumulative fitness score of -3.248 for p.Gly282Ter, indicating severely depleted phosphatase activity and meeting the PTEN VCEP PS3_Moderate threshold of <= -1.11.2 PM2 (Supporting): The variant is absent from gnomAD v2.1 and has an allele frequency of 0 in gnomAD v4.1 (0/1,609,868 alleles), satisfying the PTEN VCEP PM2_Supporting criterion of <0.00001 (0.001%).3 PM1 not met: Codon 282 lies outside the PTEN catalytic motifs (residues 90-94, 123-130, 166-168) and is not in a statistically significant mutational hotspot.4 Combined classification: 1 Very Strong (PVS1) + 1 Moderate (PS3) + 1 Supporting (PM2) meets PTEN VCEP Rule 10 (Likely Pathogenic). Insufficient evidence for Pathogenic: no Strong-level criteria met, and only 1 Supporting criterion (Rule 4 requires >=2 Supporting for Pathogenic with PVS1).5
PTEN
Final classification
Pathogenic
PVS1PS3PM2
PTEN
c.844G>T
p.Gly282Ter
This variant
PVS1 (Very Strong): c.844G>T is a nonsense variant producing a premature termination codon at position 282 (p.Gly282Ter), located well 5' to the p.D375 threshold in exon 8 of the biologically-relevant transcript NM_000314.8. Per the PTEN VCEP decision tree, this is predicted to undergo NMD and is assigned PVS1 at Very Strong strength.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule3 (1 Pathogenic.Very Strong + 1 Pathogenic.Moderate + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PS3 moderate, PM2 supporting; maps to Pathogenic.
Classification rationale
PVS1PS3PM2
Pathogenic
PTEN c.844G>T
PVS1 + PS3 + PM2
→
Pathogenic
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 14 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Nonsense variant at codon 282 (c.844G>T, p.Gly282Ter) in exon 8 of PTEN (NM_000314.8). The stop codon occurs well 5' to the p.D375 (c.1121) positional threshold and is predicted to undergo nonsense-mediated decay. Per the PTEN VCEP PVS1 decision tree, a nonsense variant with stop codon at or 5' to p.D375 in the biologically-relevant transcript NM_000314.8 is assigned PVS1 at Very Strong strength.
PTEN VCEP PVS1 decision tree assigns PVS1 (Very Strong) to nonsense variants with stop codon at or 5' to p.D375 (c.1121) in transcript NM_000314.8Codon 282 is well 5' to the p.D375 (codon 375c.1121) positional threshold
✓
PS3
moderate
Pathogenic
The Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional assay reports a cumulative fitness score of -3.248 for p.Gly282Ter, which is well below the PTEN VCEP PS3_Moderate threshold of <= -1.11. This indicates severely depleted phosphatase activity, confirming a damaging effect on the gene product.
Mighell et al. 2018 saturation mutagenesis: G282* (Gly282Ter) Cum_score = -3.248High_conf = TrueCum_score <= -1.11 meets PTEN VCEP PS3_Moderate threshold
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and has an allele frequency of 0 in gnomAD v4.1 (0/1,609,868 alleles), meeting the PTEN VCEP PM2_Supporting threshold of <0.00001 (0.001%). No subpopulation exceeds the 0.00002 (0.002%) threshold.
gnomAD v2.1: absentgnomAD v4.1: AF = 0.00000% (0/1609
Assessed · not applied
· 7 not met · 7 not assessed
Pathogenic
PS1
No previously established pathogenic variant resulting in the same amino acid change (p.Gly282Ter) was identified in ClinVar or the literature.
PS2
No de novo observation data are available.
PS4
No proband or case-control data are available to calculate a specificity score or compare variant prevalence in affected individuals versus controls.
PM1
Codon 282 is not located within any of the PTEN VCEP-specified catalytic motifs (residues 90-94, 123-130, 166-168 per NP_000305.3).
PM6
No de novo observations are reported for this variant.
PP1
No co-segregation data are available.
Benign
BA1
The PTEN VCEP BA1 threshold requires a gnomAD filtering allele frequency > 0.00056 (0.056%).
BS1
The PTEN VCEP BS1_Strong threshold requires a gnomAD filtering allele frequency from 0.000043 (0.0043%) to 0.00056 (0.056%).
BS2
No homozygous observations are reported in gnomAD.
BS3
The Mighell et al.
BS4
No segregation data are available to evaluate lack of segregation in affected family members.
BP2
No evidence is available regarding observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/phase unknown with multiple pathogenic/likely pathogenic PTEN variants.
BP4
The PTEN VCEP BP4 specifies REVEL score < 0.5 for missense variants, but REVEL is not available for this nonsense variant.
BP5
No evidence is available regarding an alternate molecular basis for disease in a patient carrying this variant.
N/A · 8
PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1609868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/73486 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,609,868
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.652534.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64292277, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 3 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR