About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.956del, p.(Thr319IlefsTer2)
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 frameshift, NM_000314.8:c.956del, predicted to cause p.(Thr319IlefsTer2) [p.(T319Ifs*2)] and truncate PTEN in exon 8 before the PTEN-specific p.D375 (c.1121) threshold. Under the PTEN-specific PVS1 decision tree, truncating variants at or 5' to this threshold in the biologically relevant transcript are assigned PVS1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of less than 0.00001 (0.001%) allele frequency and consistent with rarity in population databases.
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
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 2 not met · 10 not assessed · 14 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.956del (p.Thr319IlefsTer2; p.T319Ifs*2) variant has been reported in ClinVar as Pathogenic by one clinical laboratory.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases and meeting the PTEN PM2_Supporting threshold of less than 0.00001 (0.001%).
This frameshift is predicted to truncate PTEN at codon 320 in exon 8, and the PTEN-specific PVS1 decision tree assigns PVS1 to truncating variants at or 5' to p.D375 (c.1121) in transcript NM_000314.8.
SpliceAI predicts no significant splice effect for this variant (max delta score 0.02), and REVEL and BayesDel are not applicable because this is not a single-nucleotide missense variant.
No criteria match.
Met · 2
PVS1 Very strongThis variant is a frameshift, NM_000314.8:c.956del, predicted to cause p.(Thr319IlefsTer2) [p.(T319Ifs*2)] and truncate PTEN in exon 8 before the PTEN-specific p.D375 (c.1121) threshold. Under the PTEN-specific PVS1 decision tree, truncating variants at or 5' to this threshold in the biologically relevant transcript are assigned PVS1. Details ▾Hide ▴
Rule
PTEN-specific PVS1 decision tree: truncating variant at or 5' to p.D375 (c.1121) in NM_000314.8 -> PVS1
Evidence considered
- Frameshift consequence p.(Thr319IlefsTer2) [p.(T319Ifs*2)]
- PTEN loss of function is an established disease mechanism
- PTEN-specific PVS1 threshold at p.D375 (c.1121)
- Variant lies in exon 8 and is upstream of the threshold
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of less than 0.00001 (0.001%) allele frequency and consistent with rarity in population databases. Details ▾Hide ▴
Rule
Absent or below the PTEN population threshold in large population datasets
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- PTEN PM2 threshold <0.00001
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the PTEN BA1 threshold of greater than 0.00056 (0.056%). Details ▾Hide ▴
Rule
Population frequency above PTEN BA1 threshold
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BA1 threshold >0.00056
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and is therefore below the PTEN BS1 thresholds of 0.0000043 to 0.00056. Details ▾Hide ▴
Rule
Population frequency in the PTEN BS1 range
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BS1 supporting and strong frequency thresholds not reached
Sources
Not assessed · 10 · no assessment recorded
PS2 No confirmed de novo observation with maternity and paternity established was identified for this variant. Details ▾Hide ▴
PS3 No PTEN functional study meeting the PTEN Expert Panel PS3 rules was identified for this variant. The available PTEN saturation mutagenesis resource is intended for missense phosphatase activity assessment, and no RNA assay showing an abnormal splicing effect was identified. Details ▾Hide ▴
Rule
PTEN PS3 requires a qualifying functional or RNA assay showing a damaging effect
Evidence considered
- PTEN missense functional dataset is not applicable to a frameshift variant
- No RNA functional assay identified
- SpliceAI max delta score 0.02 does not provide PS3 evidence
Still missing
- Published RNA or other PTEN functional assay data specific to this variant
Sources
PS4 This variant has a single ClinVar pathogenic submission, but no counted series of unrelated affected individuals, specificity score, or case-control enrichment data were identified to meet the PTEN PS4 rule. Details ▾Hide ▴
PM6 No presumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Assumed de novo occurrence in a patient with the disease and no family history
Evidence considered
- No inheritance details supporting presumed de novo status
Still missing
- Case-level evidence showing assumed de novo occurrence in an affected individual with no family history
Sources
PP1 No segregation data were identified showing this variant tracking with PTEN-related disease in informative relatives. Details ▾Hide ▴
BS2 No observation of this variant in a healthy or PTEN hamartoma tumor syndrome-unaffected homozygous individual was identified. Details ▾Hide ▴
Rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual
Evidence considered
- Variant absent from gnomAD
- No homozygous unaffected observations identified
Still missing
- Documented homozygous observation in a healthy or PHTS-unaffected individual
Sources
BS3 No well-established PTEN functional study showing no damaging effect was identified for this variant. The available PTEN saturation mutagenesis resource is intended for missense variants and does not provide benign functional evidence for this frameshift. Details ▾Hide ▴
Rule
Well-established functional evidence showing no damaging effect
Evidence considered
- PTEN missense functional dataset not applicable to this frameshift
Still missing
- Published functional data showing no damaging effect for this specific variant
Sources
cspec ↗vcep_mmc2
BS4 No lack-of-segregation data were identified for this variant in one or more families. Details ▾Hide ▴
BP2 No data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with qualifying pathogenic PTEN variants. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic PTEN variant or qualifying repeated cis/phase-unknown observations
Evidence considered
- No phase observations identified
Still missing
- Phase data with another pathogenic or likely pathogenic PTEN variant
Sources
BP5 No alternate molecular diagnosis was identified that would explain the phenotype without overlap with PTEN-related disease. Details ▾Hide ▴
Rule
Alternate molecular basis for disease with no overlap with PTEN-related phenotype
Evidence considered
- No alternate molecular basis identified
Still missing
- Independent molecular diagnosis and clinical correlation excluding PTEN-related overlap
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to the same amino acid change as a previously established pathogenic variant. This variant is a frameshift, not a missense or equivalent same-amino-acid substitution. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant
Evidence considered
- Frameshift consequence rather than amino acid substitution
Sources
PM1 N/APM1 in the PTEN specification is used for variants in defined catalytic motifs and hotspot functional regions. This variant is a frameshift at codon 319 and does not fit the PTEN PM1 missense-domain rule. Details ▾Hide ▴
Rule
Located in a PTEN mutational hotspot or critical catalytic motif
Evidence considered
- PTEN PM1 catalytic motifs are residues 90-94
- 123-130
- and 166-168
- No hotspot row was identified for residue T319
Sources
PM3 VCEPPM3 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
PM4 N/APM4 in the PTEN specification applies to in-frame insertions or deletions affecting specified motifs or to stop-loss variants. This variant is a frameshift with a premature termination codon, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length change due to in-frame indel or stop-loss
Evidence considered
- Frameshift rather than in-frame indel or stop-loss
Sources
PM5 N/APM5 in the PTEN specification uses classic same-residue missense logic. This variant is a frameshift, and the PM5 candidate review determined that classic missense PM5 is not applicable. Details ▾Hide ▴
Rule
Different pathogenic missense change at the same residue
Evidence considered
- Variant is not missense-like
- PM5 candidate review marked the criterion not applicable
Sources
cspec ↗pm5_candidates
PP2 N/APP2 applies to missense variation. This variant is a frameshift. Details ▾Hide ▴
Rule
Missense variant in a gene with low benign missense rate and common missense disease mechanism
Evidence considered
- Frameshift consequence
Sources
PP3 N/APP3 in the PTEN specification is used for splicing variants with concordant splice predictors or missense variants with REVEL greater than 0.7. This variant is a frameshift, REVEL and BayesDel were not applicable, and SpliceAI showed no significant splice effect with a max delta score of 0.02. Details ▾Hide ▴
Rule
PTEN PP3 applies to qualifying missense or splicing computational evidence
Evidence considered
- SpliceAI max delta score 0.02
- REVEL not available for this non-SNV
- BayesDel not available for this non-SNV
Sources
PP4 VCEPPP4 is not applicable in the PTEN Expert Panel specification because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP4 N/ABP4 in the PTEN specification is used for synonymous or intronic variants with benign splice predictions or missense variants with REVEL less than 0.5. This variant is a frameshift, and although SpliceAI predicts no significant splice impact with a max delta score of 0.02, that does not make BP4 applicable to a truncating coding deletion. Details ▾Hide ▴
Rule
PTEN BP4 applies to qualifying missense, synonymous, or intronic computational evidence
Evidence considered
- Frameshift consequence
- SpliceAI max delta score 0.02
- No REVEL score because the variant is not an SNV
Sources
BP6 VCEPBP6 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or qualifying intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant with no predicted splice impact
Evidence considered
- Coding frameshift deletion
- SpliceAI max delta score 0.02
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.956del
- Protein (HGVS p.)
- NP_000305.3:p.(Thr319IlefsTer2)
- GRCh38
- chr10:87961047 AC>A
- GRCh37
- chr10:89720804 AC>A
- ClinVar
- 4056230, 428201
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
- Not available
How the predictions were used
PP3 N/APP3 in the PTEN specification is used for splicing variants with concordant splice predictors or missense variants with REVEL greater than 0.7. This variant is a frameshift, REVEL and BayesDel were not applicable, and SpliceAI showed no significant splice effect with a max delta score of 0.02. Details ▾Hide ▴
Rule
PTEN PP3 applies to qualifying missense or splicing computational evidence
Evidence considered
- SpliceAI max delta score 0.02
- REVEL not available for this non-SNV
- BayesDel not available for this non-SNV
Sources
BP4 N/ABP4 in the PTEN specification is used for synonymous or intronic variants with benign splice predictions or missense variants with REVEL less than 0.5. This variant is a frameshift, and although SpliceAI predicts no significant splice impact with a max delta score of 0.02, that does not make BP4 applicable to a truncating coding deletion. Details ▾Hide ▴
Rule
PTEN BP4 applies to qualifying missense, synonymous, or intronic computational evidence
Evidence considered
- Frameshift consequence
- SpliceAI max delta score 0.02
- No REVEL score because the variant is not an SNV
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants with no predicted splice impact. This variant is a coding frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or qualifying intronic variant with no predicted splice impact
Evidence considered
- Coding frameshift deletion
- SpliceAI max delta score 0.02
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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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.
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PMID 20301661 ↗PTEN Hamartoma Tumor Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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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.
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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.
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 0.020
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/4056230/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89720804-AC-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87961047-AC-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.956d…
- OncoKB ↗www.oncokb.org/gene/PTEN/T319Ifs*2
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.956del
- 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 = 4056230)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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.