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
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.955_956dup
p.Thr321Ter
This variant
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 ↗
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 · 2 applied · 16 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
Very Strong
review
Pathogenic
Using the PTEN-specific PVS1 decision tree, NM_000314.8:c.955_956dup is a null variant that introduces a premature termination codon at p.(Thr321Ter), which is 5' of the PTEN NMD cutoff at p.D375 (c.1121); this supports PVS1 at Very Strong strength.
NM_000314.8:c.955_956dup normalizes to NP_000305.3:p.(Thr321Ter) / p.(T321*)PTEN PVS1 decision tree assigns PVS1 to stop codons or disruption at or 5' to p.D375 (c.1121) in NM_000314.8
PM2
Supporting
review
Pathogenic
The variant is absent from both gnomAD v2.1 and gnomAD v4.1, satisfying the PTEN PM2_Supporting rule for an ultra-rare or absent allele in population databases.
Absent from gnomAD v2.1Absent from gnomAD v4.1
Assessed · not applied
· 3 not met · 13 not assessed
Pathogenic
PS1
No prior pathogenic variant with the same amino acid change or qualifying same-nucleotide pathogenic splice comparator was documented in the reviewed workspace.
PS2
No confirmed de novo observation with maternity and paternity confirmation was present in the workspace.
PS3
No variant-specific functional study meeting PTEN PS3 rules was identified.
PS4
No proband-count, phenotype-specificity score, or case-control enrichment data sufficient for PTEN PS4 were assembled in the workspace.
PM1
PTEN PM1 is restricted to catalytic motif residues 90-94, 123-130, and 166-168.
PM6
No assumed de novo observation without parental confirmation was documented in the workspace.
PP1
No segregation data across informative meioses were provided for PP1 assessment.
PP3
PTEN PP3 requires concordant splicing predictors for qualifying splicing variants or REVEL >0.7 for missense variants.
Benign
BA1
The variant is absent from gnomAD and therefore does not meet the PTEN BA1 population threshold.
BS1
The variant is absent from gnomAD and does not reach the PTEN BS1 supporting or strong frequency ranges.
BS2
No homozygous observations in healthy or PTEN-hamartoma-spectrum-unaffected individuals were provided.
BS3
No variant-specific functional evidence showing no damaging effect was identified.
BS4
No segregation dataset demonstrating lack of segregation in one or more families was present.
BP2
No phase data or observations with other pathogenic/likely pathogenic PTEN variants were assembled for BP2 assessment.
BP4
PTEN BP4 requires concordant benign splicing prediction for qualifying splicing variants or REVEL <0.5 for missense variants.
BP5
No evidence of an alternate highly penetrant molecular diagnosis with non-overlapping phenotype was assembled.
N/A · 10
PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
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