The PTEN c.955_956dup (p.Thr321Ter; p.T321*) variant has not been observed in somatic cancers in COSMIC, has not been reported in ClinVar, and is listed by OncoKB as Likely Oncogenic with a likely loss-of-function effect.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting PTEN PM2 at Supporting strength.2 PTEN-specific null-variant guidance supports PVS1 at Very Strong strength because this duplication introduces a premature termination codon at p.Thr321, which is upstream of the PTEN p.D375 (c.1121) NMD cutoff in transcript NM_000314.8.3 SpliceAI predicts no significant splice effect for NM_000314.8:c.955_956dup (max delta score 0.01), and the residue is outside the PTEN PM1 catalytic motifs with no Cancer Hotspots signal at T321.4
PTEN
Final classification
Likely Pathogenic
PTEN c.955_956dup · p.Thr321Ter
PTEN
The PTEN c.955_956dup (p.Thr321Ter; p.T321*) variant has not been observed in somatic cancers in COSMIC, has not been reported in ClinVar, and is listed by OncoKB as Likely Oncogenic with a likely loss-of-function effect.
Applied the explicit PTEN CSPEC/VCEP final-classification framework from final_classification_framework.json (cspec_ruleset criteria-combination framework), not generic ACMG combination rules.
Classification rationale
PVS1PM2
Likely Pathogenic
PTEN c.955_956dup
PVS1 + PM2
→
Likely Pathogenic
3
cspec ↗vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___p_t_e_n
4
spliceai ↗hotspotscspec ↗
Gene diagram
· NM_000314.8 · variants mapped to exon structure
PTEN
NM_000314.8
Fetching transcript structure from UCSC…
Applied criteria · 2 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
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
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 = 0.01).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links