The PTEN-specific PVS1 decision tree supports PVS1_Strong for this canonical splice acceptor variant because it affects the exon 9 acceptor of NM_000314.8, and preserved-frame loss of entire exon 9 is explicitly treated as a critical altered region in PTEN.1 PS1_Strong is met because ClinVar contains a same-nucleotide pathogenic splicing variant at NM_000314.8:c.1027-1G>A.2 The queried variant shows equal predicted splice acceptor loss to the known pathogenic same-position variant by SpliceAI (DS_AL 0.99), satisfying the PTEN same-position splicing use of PS1.3 PM2_Supporting is met because the variant is absent from both gnomAD v2.1 and gnomAD v4.1.4 No assembled RNA assay, de novo series, segregation dataset, or PTEN PS4 phenotype-scored case series was available to upgrade beyond the current evidence combination.5
PTEN
Final classification
Likely Pathogenic
PTEN c.1027-1G>C · p.?
PTEN
The PTEN-specific PVS1 decision tree supports PVS1_Strong for this canonical splice acceptor variant because it affects the exon 9 acceptor of NM_000314.8, and preserved-frame loss of entire exon 9 is explicitly treated as a critical altered region in PTEN.
PTEN VCEP v3.2.0 ACMG/AMP categorical combination: PVS1_Strong + PS1_Strong + PM2_Supporting.
Classification rationale
PVS1PS1PM2
Likely Pathogenic
PTEN c.1027-1G>C
PVS1 + PS1 + PM2
→
Likely 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
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV64298429, n = 5 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links