About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.304A>T, p.(Lys102Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen PTEN VCEP v3.2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
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.
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 2
PVS1 Very strongThis 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. Details ▾Hide ▴
Rule
PTEN VCEP PVS1 decision tree: nonsense/stop variants at or 5' to p.D375 in NM_000314.8 qualify for PVS1.
Evidence considered
- PTEN VCEP PVS1 decision tree threshold at p.D375 (c.1121)
- Variant consequence p.Lys102Ter/p.K102* in NM_000314.8
- PTEN loss of function established as a disease mechanism in the applied framework
Sources
PM2 SupportingThis 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. Details ▾Hide ▴
Rule
Absent from population databases or allele frequency <0.001% in gnomAD/another large population database.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- PTEN VCEP PM2 threshold <0.001%
Sources
Not met · 4 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar exact variant record reviewed
- PTEN VCEP PS1 rule requires the same amino acid change as an established pathogenic variant
Still missing
- A targeted search for alternate nucleotide changes yielding the same stop codon could further confirm this assessment.
Sources
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. PM1 is not met. Details ▾Hide ▴
Rule
Located in a mutational hot spot and/or critical well-established functional domain.
Evidence considered
- PTEN PM1 catalytic motif ranges
- Cancer Hotspots review did not identify a significant hotspot at K102
Sources
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%. BA1 is not met. Details ▾Hide ▴
Rule
gnomAD filtering allele frequency >0.056%.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- PTEN BA1 threshold >0.056%
Sources
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. BS1 is not met. Details ▾Hide ▴
Rule
Allele frequency between PTEN BS1 thresholds in gnomAD.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- PTEN BS1 thresholds 0.00043%-0.0043% supporting and 0.0043%-0.056% strong
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified in the available evidence, so PS2 was not assessed. Details ▾Hide ▴
PS3 No well-established functional study specific to this variant was identified that demonstrates a damaging effect suitable for PTEN PS3. The PTEN VCEP functional assay file highlighted for PS3/BS3 is a missense phosphatase assay and is not directly applicable to this nonsense variant. Details ▾Hide ▴
Rule
Well-established functional studies supportive of a damaging effect on the gene or gene product.
Evidence considered
- PTEN VCEP PS3 specifications
- Mighell et al. assay file indexed for missense variants
Still missing
- Variant-specific RNA or other functional data would be needed to assess PS3.
Sources
cspec ↗vcep_mmc2
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. Details ▾Hide ▴
Rule
Increased prevalence in affected individuals or sufficient proband specificity score.
Evidence considered
- ClinVar exact variant summary reviewed
- PTEN VCEP PS4 specificity-score framework
Still missing
- Exact proband counts with PTEN-specific phenotype specificity scoring would be needed to apply PS4.
Sources
PM6 No assumed de novo occurrence without confirmed parentage was identified in the available evidence, so PM6 was not assessed. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
BS2 No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified in the available evidence, so BS2 was not assessed. Details ▾Hide ▴
Rule
Observed in the homozygous state in a healthy or PTEN-unaffected individual.
Evidence considered
- Population summaries did not show BS2-level observations
Still missing
- Documented homozygous or unaffected observations would be needed to apply BS2.
Sources
BS3 No well-established functional study showing no damaging effect for this variant was identified. The PTEN VCEP functional assay file indexed for BS3 is a missense phosphatase assay and is not directly applicable to this nonsense variant. Details ▾Hide ▴
Rule
Well-established functional studies show no damaging effect on protein function.
Evidence considered
- PTEN VCEP BS3 specifications
- Mighell et al. assay file indexed for missense variants
Still missing
- Variant-specific functional data showing preserved function would be needed to assess BS3.
Sources
cspec ↗vcep_mmc2
BS4 No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
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. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic variant or sufficient cis/phase-unknown observations with pathogenic variants.
Evidence considered
- Available exact-variant summaries did not provide co-occurrence data
Still missing
- Phase and co-occurrence data would be needed to evaluate BP2.
Sources
BP5 No alternate molecular diagnosis with a non-overlapping phenotype was identified in the available evidence, so BP5 was not assessed. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease and non-overlapping phenotype.
Evidence considered
- No alternate molecular basis documented in the available evidence
Still missing
- Detailed clinical and alternate-diagnosis information would be needed to evaluate BP5.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable in the PTEN framework for this autosomal dominant condition. Details ▾Hide ▴
PM4 N/APM4 applies to in-frame protein length changes or stop-loss variants. This variant is a nonsense change and is assessed under PVS1 rather than PM4. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- Variant consequence is nonsense
- not in-frame indel or stop-loss
Sources
PM5 N/APM5 is a missense criterion and does not apply to this nonsense variant. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- Variant consequence is nonsense
Sources
PP2 N/APP2 is a missense criterion and does not apply to this nonsense variant. Details ▾Hide ▴
Rule
Missense variant in a gene with low benign missense variation and where missense variants are a common mechanism of disease.
Evidence considered
- Variant consequence is nonsense
Sources
PP3 N/APTEN PP3 is specified for missense variants with REVEL >0.7 or for splicing variants with concordant splice predictions. This variant is a nonsense change, REVEL was not available, SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, and the available BayesDel score of 0.652534 is not used by the PTEN VCEP PP3 rule for this variant type. PP3 is not applicable. Details ▾Hide ▴
Rule
Missense REVEL >0.7 or splicing variants with concordant splice predictions.
Evidence considered
- SpliceAI max delta 0.04
- REVEL not found
- BayesDel 0.652534 available but outside PTEN VCEP PP3 rule for nonsense variants
Sources
PP4 N/APP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP4 N/APTEN BP4 is specified for missense variants with REVEL <0.5 or for synonymous/intronic splicing variants with benign splice predictions. This variant is a nonsense change. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, BP4 is not the applicable criterion for this variant type. Details ▾Hide ▴
Rule
Missense REVEL <0.5 or splicing variants with benign computational predictions.
Evidence considered
- SpliceAI max delta 0.04
- BayesDel 0.652534 available but not part of PTEN BP4 rule for nonsense variants
Sources
BP6 N/ABP6 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or deep intronic variants with no predicted splicing effect. This variant is a nonsense coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or intronic variant with no predicted splicing impact.
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta 0.04 reviewed but BP7 is restricted to synonymous/intronic variants
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.304A>T
- Protein (HGVS p.)
- NP_000305.3:p.(Lys102Ter)
- GRCh38
- chr10:87933063 A>T
- GRCh37
- chr10:89692820 A>T
Gene diagram
Every interpreted variant in PTEN, mapped onto the exon structure of NM_000314.8. Select a row to find it on the plot.
PTENNM_000314.8
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PTEN
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/APTEN PP3 is specified for missense variants with REVEL >0.7 or for splicing variants with concordant splice predictions. This variant is a nonsense change, REVEL was not available, SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, and the available BayesDel score of 0.652534 is not used by the PTEN VCEP PP3 rule for this variant type. PP3 is not applicable. Details ▾Hide ▴
Rule
Missense REVEL >0.7 or splicing variants with concordant splice predictions.
Evidence considered
- SpliceAI max delta 0.04
- REVEL not found
- BayesDel 0.652534 available but outside PTEN VCEP PP3 rule for nonsense variants
Sources
BP4 N/APTEN BP4 is specified for missense variants with REVEL <0.5 or for synonymous/intronic splicing variants with benign splice predictions. This variant is a nonsense change. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, BP4 is not the applicable criterion for this variant type. Details ▾Hide ▴
Rule
Missense REVEL <0.5 or splicing variants with benign computational predictions.
Evidence considered
- SpliceAI max delta 0.04
- BayesDel 0.652534 available but not part of PTEN BP4 rule for nonsense variants
Sources
BP7 N/ABP7 applies to synonymous or deep intronic variants with no predicted splicing effect. This variant is a nonsense coding change, so BP7 is not applicable. Details ▾Hide ▴
Rule
Synonymous or intronic variant with no predicted splicing impact.
Evidence considered
- Variant consequence is nonsense
- SpliceAI max delta 0.04 reviewed but BP7 is restricted to synonymous/intronic variants
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.652534.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/135637575
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1074078/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692820-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933063-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.304A…
- OncoKB ↗www.oncokb.org/gene/PTEN/K102*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/login
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). BayesDel score = 0.652534.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.