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
Final classification
Likely Pathogenic
PVS1PM2
PTEN
c.304A>T
p.Lys102Ter
This variant
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 ↗
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 · 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
Pathogenic
This variant is a nonsense change, NM_000314.8:c.304A>T (p.Lys102Ter/p.K102*), in the biologically relevant PTEN transcript. Under the PTEN-specific PVS1 decision tree, a stop codon at or 5' to p.D375 (c.1121) is assigned PVS1; this stop at codon 102 is well upstream of that threshold and is consistent with a loss-of-function allele.
PTEN VCEP PVS1 decision tree threshold at p.D375 (c.1121)Variant consequence p.Lys102Ter/p.K102* in NM_000314.8PTEN loss of function established as a disease mechanism in the applied framework
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Under the PTEN VCEP PM2 rule, absence or an allele frequency below 0.001% supports PM2_Supporting; the observed frequency is 0, which is below that threshold.
gnomAD v2.1 absentgnomAD v4.1 absentPTEN VCEP PM2 threshold <0.001%
Assessed · not applied
· 4 not met · 10 not assessed
Pathogenic
PS1
No previously established pathogenic variant producing the same amino acid change by a different nucleotide change was identified in the available evidence, so PS1 is not met.
PS2
No confirmed de novo occurrence with maternity and paternity established was identified in the available evidence, so PS2 was not assessed.
PS3
No well-established functional study specific to this variant was identified that demonstrates a damaging effect suitable for PTEN PS3.
PS4
The available evidence does not establish a confirmed count of unrelated affected probands or a case-control enrichment for this variant, so PS4 was not assessed.
PM1
This variant is at codon 102, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168), and no statistically significant hotspot evidence was identified for this site.
PM6
No assumed de novo occurrence without confirmed parentage was identified in the available evidence, so PM6 was not assessed.
PP1
No segregation data were identified for this variant, so PP1 was not assessed.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its allele frequency is well below the PTEN BA1 threshold of >0.056%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its allele frequency is below the PTEN BS1 thresholds of 0.00043% for supporting and 0.0043% for strong evidence.
BS2
No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified in the available evidence, so BS2 was not assessed.
BS3
No well-established functional study showing no damaging effect for this variant was identified.
BS4
No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.
BP2
No evidence was identified that this variant has been observed in trans with a pathogenic PTEN variant or in cis/phase unknown with multiple pathogenic PTEN variants, so BP2 was not assessed.
BP5
No alternate molecular diagnosis with a non-overlapping phenotype was identified in the available evidence, so BP5 was not assessed.
N/A · 12
PM3 · PM4 · PM5 · PP2 · PP3 · PP4 · PP5 · BP1 · BP3 · BP4 · 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 = 0.04). 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