About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.416T>G, p.(Leu139Ter)
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.416T>G (p.(Leu139Ter)), predicted to truncate PTEN early in the coding sequence. Under the PTEN-specific PVS1 decision tree, truncating variants at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 are assigned PVS1, and Leu139Ter is upstream of that threshold.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. This is below the PTEN VCEP PM2 threshold of <0.00001 (0.001%) allele frequency and supports PM2_Supporting.
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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic.
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
6 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64297098, n = 6 times).
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 c.416T>G (p.(Leu139Ter)) variant has been observed in somatic cancers (COSMIC COSV64297098, n=6) and has been reported in ClinVar as pathogenic by a single submitter.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the PTEN VCEP PM2_Supporting rarity threshold of less than 0.001% allele frequency.
This variant introduces a premature stop codon at Leu139, and under the PTEN-specific PVS1 decision tree truncating variants at or 5' to p.D375 in transcript NM_000314.8 are assigned PVS1; SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a nonsense change, NM_000314.8:c.416T>G (p.(Leu139Ter)), predicted to truncate PTEN early in the coding sequence. Under the PTEN-specific PVS1 decision tree, truncating variants at or 5' to p.D375 (c.1121) in biologically relevant transcript NM_000314.8 are assigned PVS1, and Leu139Ter is upstream of that threshold. Details ▾Hide ▴
Rule
PTEN VCEP PVS1 decision tree: truncating variants at or 5' to p.D375 in NM_000314.8 qualify for PVS1.
Evidence considered
- Nonsense consequence p.(Leu139Ter)
- PTEN-specific PVS1 decision tree threshold at p.D375 (c.1121)
- PTEN loss of function is an established disease mechanism in the VCEP framework
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. This is below the PTEN VCEP PM2 threshold of <0.00001 (0.001%) allele frequency and supports PM2_Supporting. Details ▾Hide ▴
Rule
PTEN VCEP PM2_Supporting: allele frequency <0.00001 (0.001%) or absent in large population databases.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
Not met · 4 · evaluated, threshold not reached
PM1 This variant is not located in a PTEN catalytic motif defined for PM1. PTEN VCEP PM1 is limited to residues 90-94, 123-130, and 166-168, and Cancer Hotspots did not identify L139 as a statistically significant hotspot. Details ▾Hide ▴
Rule
PTEN VCEP PM1 applies to residues 90-94, 123-130, and 166-168.
Evidence considered
- PTEN VCEP PM1 catalytic motif definition
- No hotspot detected at residue L139
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN VCEP BA1 threshold of >0.00056 (0.056%). Details ▾Hide ▴
Rule
PTEN VCEP BA1 requires filtering allele frequency >0.00056 (0.056%).
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the PTEN VCEP BS1 thresholds of 0.0000043-0.00056 allele frequency. Details ▾Hide ▴
Rule
PTEN VCEP BS1 requires allele frequency from 0.0000043 to 0.00056, depending on strength.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
BS2 No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified for this variant, so BS2 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP BS2 requires homozygous observations in healthy or unaffected individuals.
Evidence considered
- No homozygous population observation identified
Sources
Not assessed · 10 · no assessment recorded
PS1 No prior pathogenic variant with a different nucleotide change producing the same amino acid change was identified in the reviewed evidence, so PS1 was not applied. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar exact-variant record only
Still missing
- A codon-level search for alternative nucleotide changes causing the same protein effect would be needed to support PS1.
Sources
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 was not applied. Details ▾Hide ▴
Rule
PS2 requires confirmed de novo occurrence in a patient with the disease and no family history.
Evidence considered
- No de novo case evidence in the reviewed materials
Still missing
- Need a published or submitter-level confirmed de novo observation in an affected individual with no family history.
Sources
PS3 No variant-specific functional study meeting the PTEN VCEP PS3 rules was identified for this nonsense variant. The PTEN VCEP phosphatase activity framework in Mighell et al. applies to missense variants, and no RNA or other assay demonstrating an abnormal effect specific to this variant was available. Details ▾Hide ▴
Rule
PTEN VCEP PS3 uses RNA/splicing assays or accepted functional assays; Mighell phosphatase activity thresholds are specified for missense variants.
Evidence considered
- PTEN VCEP PS3 specifications
- Mighell et al. missense assay resource
Still missing
- Need a variant-specific RNA
- cellular
- or other accepted functional study.
Sources
cspec ↗vcep_mmc2
PS4 This variant has been reported in ClinVar and in somatic cancers in COSMIC, but no countable germline proband data or case-control enrichment meeting the PTEN VCEP PS4 rules were identified. The available observations are therefore insufficient to apply PS4. Details ▾Hide ▴
Rule
PTEN VCEP PS4 requires specified proband scoring or significantly increased prevalence in affected individuals.
Evidence considered
- ClinVar pathogenic submission
- COSMIC somatic count of 6
Still missing
- Need countable affected germline observations with PTEN-specific phenotype scoring or formal enrichment versus controls.
Sources
PM6 No presumed de novo observation without parental confirmation was identified for this variant, so PM6 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP PM6 requires specified assumed de novo observations.
Evidence considered
- No presumed de novo evidence in the reviewed materials
Still missing
- Need a reported assumed de novo occurrence in an affected individual with no family history.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP PP1 requires co-segregation with disease in multiple affected family members.
Evidence considered
- No pedigree or segregation evidence in the reviewed materials
Still missing
- Need informative family segregation data with 3 or more meioses for PP1_Supporting or higher.
Sources
BS3 No well-established functional study showing no damaging effect for this variant was identified. The PTEN VCEP benign phosphatase activity framework in Mighell et al. applies to missense variants, and no variant-specific benign functional evidence was available for this nonsense variant. Details ▾Hide ▴
Rule
PTEN VCEP BS3 uses well-established benign functional evidence; missense phosphatase activity >0 supports BS3_Supporting.
Evidence considered
- PTEN VCEP BS3 specifications
- Mighell et al. missense assay resource
Still missing
- Need a variant-specific functional study showing no damaging effect if BS3 is to be considered.
Sources
cspec ↗vcep_mmc2
BS4 No lack-of-segregation evidence was identified for this variant, so BS4 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP BS4 requires lack of segregation in one family for supporting strength or two or more families for strong strength.
Evidence considered
- No non-segregation evidence in the reviewed materials
Still missing
- Need one or more informative families showing lack of segregation in affected individuals.
Sources
BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with multiple pathogenic PTEN variants, so BP2 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP BP2 requires specific in trans or repeated cis/phase-unknown observations with pathogenic PTEN variants.
Evidence considered
- No phasing evidence in the reviewed materials
Still missing
- Need informative phasing observations with another pathogenic or likely pathogenic PTEN variant.
Sources
BP5 No alternate highly penetrant molecular explanation with a non-overlapping phenotype was identified, so BP5 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP BP5 requires a highly penetrant alternate molecular explanation and no phenotype overlap with PTEN.
Evidence considered
- No alternate molecular diagnosis evidence in the reviewed materials
Still missing
- Need case-level data showing an alternate molecular basis for disease with no overlap with PTEN-associated phenotypes.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 VCEPPM3 is not applicable in the PTEN VCEP framework for this autosomal dominant PTEN-related context. Details ▾Hide ▴
VCEP rule
PTEN VCEP marks PM3 as not applicable.
Evidence considered
- PTEN VCEP applicability table
Sources
PM4 N/AThis variant is a nonsense change rather than an in-frame insertion/deletion or stop-loss variant, so PM4 does not apply. Details ▾Hide ▴
Rule
PTEN VCEP PM4 applies to in-frame insertions/deletions affecting specified motifs or to protein extension variants.
Evidence considered
- Variant consequence is nonsense
Sources
PM5 N/APM5 was not applied because the PTEN VCEP uses classic same-residue missense logic, and this variant is a nonsense change rather than a missense variant. Details ▾Hide ▴
Rule
PTEN VCEP PM5 applies to missense changes at a residue with a different pathogenic/likely pathogenic missense change.
Evidence considered
- PM5 framework is classic same-residue missense
- Variant class is nonsense
Sources
cspec ↗pm5_candidates
PP2 N/APP2 is a missense criterion and was not applied because this variant is a nonsense change. Details ▾Hide ▴
Rule
PP2 applies to missense variants in genes with a low rate of benign missense variation and missense as a common mechanism.
Evidence considered
- Variant consequence is nonsense
Sources
PP3 N/AAvailable computational data include SpliceAI max delta score 0.01, no REVEL score, and BayesDel 0.652534, but the PTEN VCEP PP3 rule is defined for missense variants with REVEL >0.7 or for splicing variants with concordant splice prediction. Because this variant is an early nonsense change rather than a missense or splice-region variant, PP3 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP PP3 applies to missense variants with REVEL >0.7 or to qualifying splicing variants.
Evidence considered
- SpliceAI max delta score 0.01
- No REVEL score found
- BayesDel score 0.652534
Sources
PP4 VCEPPP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4 scoring. Details ▾Hide ▴
VCEP rule
PTEN VCEP marks PP4 as not applicable.
Evidence considered
- PTEN VCEP applicability table
Sources
PP5 VCEPPP5 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
VCEP rule
PTEN VCEP marks PP5 as not applicable.
Evidence considered
- PTEN VCEP applicability table
Sources
BP1 VCEPBP1 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
VCEP rule
PTEN VCEP marks BP1 as not applicable.
Evidence considered
- PTEN VCEP applicability table
Sources
BP3 VCEPBP3 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
VCEP rule
PTEN VCEP marks BP3 as not applicable.
Evidence considered
- PTEN VCEP applicability table
Sources
BP4 N/AAvailable computational data include SpliceAI max delta score 0.01, no REVEL score, and BayesDel 0.652534, but the PTEN VCEP BP4 rule is defined for missense variants with REVEL <0.5 or for qualifying splicing variants with concordant benign splice prediction. Because this variant is a nonsense change rather than a missense or intronic/synonymous splicing candidate, BP4 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP BP4 applies to missense variants with REVEL <0.5 or to qualifying benign splicing predictions.
Evidence considered
- SpliceAI max delta score 0.01
- No REVEL score found
- BayesDel score 0.652534
Sources
BP6 VCEPBP6 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
VCEP rule
PTEN VCEP marks BP6 as not applicable.
Evidence considered
- PTEN VCEP applicability table
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, but this variant is a nonsense coding change, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN VCEP BP7 applies to synonymous or intronic variants at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Variant consequence is nonsense
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.416T>G
- Protein (HGVS p.)
- NP_000305.3:p.(Leu139Ter)
- GRCh38
- chr10:87933175 T>G
- GRCh37
- chr10:89692932 T>G
- ClinVar
- 427590
- COSMIC
- COSV64297098
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
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTEN
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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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.653
How the predictions were used
PP3 N/AAvailable computational data include SpliceAI max delta score 0.01, no REVEL score, and BayesDel 0.652534, but the PTEN VCEP PP3 rule is defined for missense variants with REVEL >0.7 or for splicing variants with concordant splice prediction. Because this variant is an early nonsense change rather than a missense or splice-region variant, PP3 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP PP3 applies to missense variants with REVEL >0.7 or to qualifying splicing variants.
Evidence considered
- SpliceAI max delta score 0.01
- No REVEL score found
- BayesDel score 0.652534
Sources
BP4 N/AAvailable computational data include SpliceAI max delta score 0.01, no REVEL score, and BayesDel 0.652534, but the PTEN VCEP BP4 rule is defined for missense variants with REVEL <0.5 or for qualifying splicing variants with concordant benign splice prediction. Because this variant is a nonsense change rather than a missense or intronic/synonymous splicing candidate, BP4 was not applied. Details ▾Hide ▴
Rule
PTEN VCEP BP4 applies to missense variants with REVEL <0.5 or to qualifying benign splicing predictions.
Evidence considered
- SpliceAI max delta score 0.01
- No REVEL score found
- BayesDel score 0.652534
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, but this variant is a nonsense coding change, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN VCEP BP7 applies to synonymous or intronic variants at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Variant consequence is nonsense
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.652534.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 11237521 ↗PTEN: life as a tumor suppressor.No paper-specific finding is recorded.
-
PMID 17218262 ↗Essential role for nuclear PTEN in maintaining chromosomal integrity.No paper-specific finding is recorded.
-
PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.No paper-specific finding is recorded.
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
-
PMID 20301661 ↗PTEN Hamartoma Tumor Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013No paper-specific finding is recorded.
-
PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013No paper-specific finding is recorded.
-
PMID 25190698 ↗Genetic/familial high-risk assessment: breast and ovarian, version 1.2014.Daly MB et al. · 2014No paper-specific finding is recorded.
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
Recorded maximum delta 0.010
Open source ↗
ClinVar
1 Pathogenic
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/427590/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692932-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933175-T-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.416T…
- OncoKB ↗www.oncokb.org/gene/PTEN/L139*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=117186634
- 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). (ClinVarID = 427590)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). 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 previously been reported in somatic cancers (COSMIC; COSV64297098, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.