The PTEN NM_000314.8:c.304A>T (p.Lys102Ter, p.K102*) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic by one clinical laboratory.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.001% and supports rarity in population databases.2 This is an early truncating PTEN variant, and under the PTEN-specific PVS1 decision tree a stop codon at codon 102 is upstream of the p.D375 (c.1121) threshold used for full-strength PVS1.3 SpliceAI predicts no significant splice effect with a maximum delta score of 0.04, and a BayesDel score of 0.652534 is available; however, the PTEN VCEP PP3/BP4 computational rules are specified for missense or defined splicing variants and were not applied to this nonsense variant.4
PTEN
Final classification
Likely Pathogenic
PTEN c.304A>T · p.Lys102Ter
PTEN
The PTEN NM_000314.8:c.304A>T (p.Lys102Ter, p.K102*) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic by one clinical laboratory.
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule20 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
PTEN c.304A>T
PVS1 + PM2
→
Likely Pathogenic
3
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_pvs1_decisiontree_pten
4
spliceai ↗bayesdelcspec ↗
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 = 0.04). 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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links