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
PTEN c.844G>T · p.Gly282Ter
PTEN
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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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