About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.525del, p.(Tyr176IlefsTer7)
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 frameshift variant, c.525del (p.Tyr176IlefsTer7), is predicted to introduce a premature termination codon well 5' of the PTEN-specific p.D375 (c.1121) threshold in biologically relevant transcript NM_000314.8, which is consistent with loss of function as an established disease mechanism for PTEN; under the PTEN PVS1 decision tree, this supports PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.00001 (0.001%) and supports PM2 at supporting strength.
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 classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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 · 3 not met · 7 not assessed · 16 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.525del (p.Tyr176IlefsTer7; p.Y176Ifs*7) variant has not been observed in COSMIC, has been reported in ClinVar as Pathogenic by one clinical laboratory, and is listed in OncoKB as Likely Oncogenic with a likely loss-of-function effect.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.00001 (0.001%) and supports PM2 at supporting strength.
This deletion causes a frameshift with premature termination at codon 176 and falls 5' of the PTEN-specific p.D375 (c.1121) PVS1 threshold in transcript NM_000314.8, supporting PVS1 as a loss-of-function variant in a gene where loss of function is an established disease mechanism.
SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.02, so no separate computational splice criterion is added.
No criteria match.
Met · 2
PVS1 Very strongThis frameshift variant, c.525del (p.Tyr176IlefsTer7), is predicted to introduce a premature termination codon well 5' of the PTEN-specific p.D375 (c.1121) threshold in biologically relevant transcript NM_000314.8, which is consistent with loss of function as an established disease mechanism for PTEN; under the PTEN PVS1 decision tree, this supports PVS1 at very strong strength. Details ▾Hide ▴
Rule
PTEN CSPEC PVS1 decision tree: frameshift with stop codon/disruption at or 5' to p.D375 (c.1121) in NM_000314.8 => PVS1
Evidence considered
- PTEN CSPEC v3.2.0 directs use of the PTEN PVS1 decision tree
- PTEN decision tree assigns PVS1 to nonsense/frameshift variants at or 5' to p.D375 (c.1121) in NM_000314.8
- Gene-level context supports PTEN loss of function as an established germline disease mechanism
- Variant-level assessment identifies this change as a frameshift with p.(Y176Ifs*7)
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.00001 (0.001%) and supports PM2 at supporting strength. Details ▾Hide ▴
Rule
PTEN CSPEC PM2_Supporting: absent or <0.00001 in population databases
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- PTEN CSPEC PM2 threshold is <0.00001 (0.001%)
Sources
Not met · 3 · evaluated, threshold not reached
PS4 This variant has been reported in ClinVar, but the available evidence does not provide the PTEN-specific proband scoring, case counts, or case-control enrichment required to apply PS4 at any strength. Details ▾Hide ▴
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the PTEN BA1 threshold of 0.00056 (0.056%). Details ▾Hide ▴
Rule
PTEN CSPEC BA1
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- PTEN CSPEC BA1 threshold is >0.00056 (0.056%)
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not fall within the PTEN BS1 supporting range of 0.0000043-0.000043 or the strong range of 0.000043-0.00056. Details ▾Hide ▴
Rule
PTEN CSPEC BS1
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- PTEN CSPEC BS1 supporting range is 0.0000043-0.000043 and strong range is 0.000043-0.00056
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
PM6 No assumed or confirmed de novo occurrence without family history was identified, so PM6 cannot be applied from the available evidence. Details ▾Hide ▴
PP1 No segregation data were identified, so PP1 cannot be applied. Details ▾Hide ▴
BS2 No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 cannot be applied. Details ▾Hide ▴
Rule
PTEN CSPEC BS2
Evidence considered
- Variant was absent from available population datasets
- No unaffected homozygous observations were provided
Still missing
- Documented homozygous observation in an unaffected individual
Sources
BS4 No lack-of-segregation evidence from one or more families was identified, so BS4 cannot be applied. Details ▾Hide ▴
BP2 No phase data showing this variant in trans with a pathogenic PTEN variant or repeated cis/phase-unknown observations with pathogenic PTEN variants were identified, so BP2 cannot be applied. Details ▾Hide ▴
BP5 No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was identified, so BP5 cannot be applied. Details ▾Hide ▴
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to the same amino acid substitution as a previously established pathogenic variant or an equivalent pathogenic splicing change; this variant is a frameshift and does not meet that rule type. Details ▾Hide ▴
Rule
PTEN CSPEC PS1
Evidence considered
- PTEN CSPEC PS1 is defined for same amino acid change or equivalent pathogenic splicing variant
Sources
PS3 N/ANo PTEN functional assay result specific to this frameshift variant was identified. The indexed PTEN functional dataset used for PS3/BS3 is a missense phosphatase assay resource and does not provide applicable evidence for this deletion. Details ▾Hide ▴
Rule
PTEN CSPEC PS3
Evidence considered
- PTEN mmc2 functional resource is indexed for missense variants
- No variant-specific RNA or protein functional assay was identified for c.525del
Still missing
- Variant-specific functional evidence
- such as an RNA or protein assay applicable to this frameshift change
Sources
cspec ↗vcep_mmc2
PM1 N/APM1 in the PTEN specification is defined for variants in established catalytic motifs at residues 90-94, 123-130, and 166-168. This frameshift occurs at Tyr176, outside those defined motifs, and is more appropriately evaluated under PVS1. Details ▾Hide ▴
Rule
PTEN CSPEC PM1
Evidence considered
- PTEN CSPEC PM1 motifs are residues 90-94
- 123-130
- and 166-168
- Cancer Hotspots did not identify a statistically significant hotspot for Y176
Sources
PM3 N/APM3 is not applicable in the PTEN specification. Details ▾Hide ▴
PM4 N/APM4 in the PTEN specification applies to in-frame insertions/deletions and stop-loss variants. This variant is a frameshift, so PM4 does not apply. Details ▾Hide ▴
Rule
PTEN CSPEC PM4
Evidence considered
- PTEN CSPEC PM4 is limited to in-frame indels and stop-loss variants
Sources
PM5 N/APM5 applies to a missense change at a residue where a different pathogenic or likely pathogenic missense change has been established. This variant is a frameshift and does not meet that rule type. Details ▾Hide ▴
Rule
PTEN CSPEC PM5
Evidence considered
- PTEN CSPEC PM5 is defined for missense variants
Sources
PP2 N/APP2 is a missense-specific rule, and this variant is a frameshift. Details ▾Hide ▴
Rule
PTEN CSPEC PP2
Evidence considered
- PTEN CSPEC PP2 is defined for missense variants
Sources
PP3 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.02), and the PTEN PP3 rule for splicing variants requires concordant splice prediction evidence. Because this is a frameshift variant already evaluated under PVS1 and no concordant splicing evidence was identified, PP3 is not applied. Details ▾Hide ▴
Rule
PTEN CSPEC PP3
Evidence considered
- SpliceAI max delta score = 0.02
- PTEN CSPEC PP3 for splicing variants requires concordant splice prediction evidence
Still missing
- Concordant splice prediction evidence or other applicable computational evidence meeting PTEN PP3 requirements
Sources
PP4 N/APP4 is not applicable in the PTEN specification. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the PTEN specification. Details ▾Hide ▴
BS3 N/ANo PTEN functional study showing no damaging effect for this frameshift variant was identified. The indexed PTEN functional assay resource applies to missense variants and does not support BS3 for this deletion. Details ▾Hide ▴
Rule
PTEN CSPEC BS3
Evidence considered
- PTEN mmc2 functional resource is indexed for missense variants
- No benign functional study specific to c.525del was identified
Still missing
- Variant-specific functional evidence showing no damaging effect
Sources
cspec ↗vcep_mmc2
BP1 N/ABP1 is not applicable in the PTEN specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the PTEN specification. Details ▾Hide ▴
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.02), but PTEN BP4 for splicing variants requires concordant computational evidence and this frameshift is not otherwise an appropriate BP4 rule type; therefore BP4 is not applied. Details ▾Hide ▴
Rule
PTEN CSPEC BP4
Evidence considered
- SpliceAI max delta score = 0.02
- PTEN CSPEC BP4 for splicing variants requires concordant prediction evidence
Still missing
- Concordant computational evidence meeting PTEN BP4 requirements for an applicable variant type
Sources
BP6 N/ABP6 is not applicable in the PTEN specification. Details ▾Hide ▴
BP7 N/ABP7 is limited to synonymous or qualifying intronic variants with no predicted splicing effect. This variant is a coding frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN CSPEC BP7
Evidence considered
- PTEN CSPEC BP7 applies to synonymous or qualifying intronic variants
- This variant is a coding frameshift deletion
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.525del
- Protein (HGVS p.)
- NP_000305.3:p.(Tyr176IlefsTer7)
- GRCh38
- chr10:87952149 TG>T
- GRCh37
- chr10:89711906 TG>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
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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.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.02), and the PTEN PP3 rule for splicing variants requires concordant splice prediction evidence. Because this is a frameshift variant already evaluated under PVS1 and no concordant splicing evidence was identified, PP3 is not applied. Details ▾Hide ▴
Rule
PTEN CSPEC PP3
Evidence considered
- SpliceAI max delta score = 0.02
- PTEN CSPEC PP3 for splicing variants requires concordant splice prediction evidence
Still missing
- Concordant splice prediction evidence or other applicable computational evidence meeting PTEN PP3 requirements
Sources
BP4 N/ASpliceAI predicts no significant splice impact for this variant (max delta score 0.02), but PTEN BP4 for splicing variants requires concordant computational evidence and this frameshift is not otherwise an appropriate BP4 rule type; therefore BP4 is not applied. Details ▾Hide ▴
Rule
PTEN CSPEC BP4
Evidence considered
- SpliceAI max delta score = 0.02
- PTEN CSPEC BP4 for splicing variants requires concordant prediction evidence
Still missing
- Concordant computational evidence meeting PTEN BP4 requirements for an applicable variant type
Sources
BP7 N/ABP7 is limited to synonymous or qualifying intronic variants with no predicted splicing effect. This variant is a coding frameshift deletion, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN CSPEC BP7
Evidence considered
- PTEN CSPEC BP7 applies to synonymous or qualifying intronic variants
- This variant is a coding frameshift deletion
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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/468695/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89711906-TG-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87952149-TG-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.525d…
- OncoKB ↗www.oncokb.org/gene/PTEN/Y176Ifs*7
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.525del
- 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 = 0.02).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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.