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
Final classification
Likely Pathogenic
PVS1PS1PM2
PTEN
c.1027-1G>C
p.?
This variant
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
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
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
Strong
Pathogenic
PTEN-specific PVS1 guidance supports PVS1_Strong for this canonical splice acceptor variant at NM_000314.8:c.1027-1G>C. The affected site is the acceptor of exon 9; exon 9 loss preserves reading frame, and the PTEN decision tree explicitly treats entire exon 9 as a critical altered region for GT-AG splice-site variants.
Variant is a canonical -1 splice acceptor change in NM_000314.8PTEN PVS1 decision tree lists preserved-frame loss of entire exon 9 as PVS1_Strong
PS1
Strong
Pathogenic
PTEN PS1_Strong is met because a different substitution at the same nucleotide position is already established as pathogenic in ClinVar (NM_000314.8:c.1027-1G>A), and SpliceAI predicts equal splice acceptor loss for the queried variant and the known pathogenic same-position variant (DS_AL 0.99 for both).
ClinVar same-position pathogenic variant: NM_000314.8:c.1027-1G>ASpliceAI acceptor-loss score for NM_000314.8:c.1027-1G>C = 0.99Equal SpliceAI acceptor-loss score was confirmed for NM_000314.8:c.1027-1G>A
PM2
Supporting
Pathogenic
PM2_Supporting is met because the variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN EP ultra-rare population threshold.
Absent from gnomAD v2.1Absent from gnomAD v4.1
Assessed · not applied
· 3 not met · 11 not assessed
Pathogenic
PS2
No confirmed de novo evidence was assembled in the reviewed workspace.
PS3
No PTEN RNA, minigene, or other splicing assay demonstrating abnormal splicing for this variant was assembled.
PS4
The workspace did not provide PTEN-scored proband phenotype specificity data or a qualifying case-control dataset to calculate PS4.
PM6
No assumed de novo evidence was assembled in the workspace.
PP1
No segregation data were assembled.
PP3
SpliceAI strongly predicts splice impact (max delta 0.99), but the PTEN EP splicing PP3 rule requires concordance of SpliceAI and VarSeak.
Benign
BA1
BA1 is not met because the variant is absent from gnomAD.
BS1
BS1 is not met because the variant is absent from gnomAD rather than exceeding PTEN benign frequency thresholds.
BS2
No homozygous observations in healthy or PTEN-unaffected individuals were assembled.
BS3
No RNA or other splicing assay demonstrating no impact on splicing was assembled.
BS4
No lack-of-segregation evidence was assembled.
BP2
No phase data with other pathogenic/likely pathogenic PTEN variants were assembled.
BP4
BP4 is not met because SpliceAI predicts strong splice impact (max delta 0.99), and PTEN BP4 for splicing additionally requires benign no-impact concordance of SpliceAI and VarSeak.
BP5
The workspace did not document at least two cases with an alternate highly penetrant diagnosis and non-overlapping PTEN phenotype.
N/A · 11
PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
Allele frequency by ancestry
three datasets · side by side
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