About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.743del, p.(Pro248LeufsTer8)
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 PTEN frameshift variant, NM_000314.8:c.743del (p.(Pro248LeufsTer8)), is predicted to create a premature termination codon at codon 255, which is well 5' of the PTEN Expert Panel p.D375 (c.1121) threshold for full-strength PVS1 in biologically relevant transcript NM_000314.8. This predicted loss-of-function effect is consistent with an established PTEN disease mechanism and meets PVS1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.00001 (0.001%) overall and below the subpopulation threshold of 0.00002 (0.002%). This 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; Rule20 applies.
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 · 11 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.743del (p.(Pro248LeufsTer8)) variant has been observed in somatic cancers in COSMIC (COSV109436597, n=2) and has been reported in ClinVar as pathogenic.
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 the general population.
The variant is a frameshift predicted to truncate PTEN at codon 255, and under the PTEN Expert Panel PVS1 decision tree this position is 5' of the p.D375 threshold for full-strength PVS1 in transcript NM_000314.8.
SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.06), and this does not alter the interpretation of the variant as a loss-of-function frameshift.
No criteria match.
Met · 2
PVS1 Very strongThis PTEN frameshift variant, NM_000314.8:c.743del (p.(Pro248LeufsTer8)), is predicted to create a premature termination codon at codon 255, which is well 5' of the PTEN Expert Panel p.D375 (c.1121) threshold for full-strength PVS1 in biologically relevant transcript NM_000314.8. This predicted loss-of-function effect is consistent with an established PTEN disease mechanism and meets PVS1. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 PVS1 decision tree: nonsense/frameshift variants at or 5' to p.D375 (c.1121) in NM_000314.8 are assigned PVS1.
Evidence considered
- NM_000314.8:c.743del is a frameshift
- Protein consequence: p.(Pro248LeufsTer8) / p.(P248Lfs*8)
- PTEN PVS1 decision tree assigns PVS1 to null variants at or 5' to p.D375 (c.1121)
- PTEN loss of function is an established disease mechanism
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2_Supporting threshold of 0.00001 (0.001%) overall and below the subpopulation threshold of 0.00002 (0.002%). This supports PM2 at supporting strength. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 PM2_Supporting.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- PTEN PM2 threshold: <0.00001 overall; if multiple alleles in a subpopulation, <0.00002
Sources
Not met · 3 · evaluated, threshold not reached
PM1 This variant affects codon 248, which is outside the PTEN catalytic motif residues 90-94, 123-130, and 166-168 defined for PM1, and it has not been shown to lie in a qualifying mutational hotspot. Available evidence does not support PM1. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 PM1.
Evidence considered
- Affected residue: 248
- PTEN PM1 motifs: residues 90-94, 123-130, 166-168
- Cancer Hotspots did not identify a statistically significant hotspot for this residue
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN BA1 threshold of greater than 0.00056 (0.056%). Available evidence does not support BA1. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BA1.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- BA1 threshold: >0.00056
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN BS1 threshold range of 0.000043 to 0.00056 for strong evidence and below 0.0000043 to 0.000043 for supporting evidence. Available evidence does not support BS1. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BS1.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- BS1 strong threshold: 0.000043 to 0.00056
- BS1 supporting threshold: 0.0000043 to 0.000043
Sources
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified that this exact protein consequence has the same amino acid change as a previously established pathogenic variant generated by a different nucleotide change, so PS1 was not assessed. Details ▾Hide ▴
PS2 No confirmed de novo occurrence with maternity and paternity established was identified, so PS2 was not assessed. Details ▾Hide ▴
PS3 No well-established functional study specific to this variant was identified that would satisfy PTEN PS3. The PTEN saturation mutagenesis phosphatase dataset cited by the Expert Panel applies to missense variants, not this frameshift variant. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 PS3.
Evidence considered
- Mighell et al. PTEN functional dataset is indexed for missense variants.
Still missing
- No variant-specific functional assay data were identified.
Sources
cspec ↗vcep_m_m_c_2
PS4 This variant has been reported in ClinVar and has been observed in somatic cancers in COSMIC, but no PTEN hamartoma tumor syndrome proband counts, specificity scores, or case-control enrichment data were identified to meet PTEN PS4. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 PS4.
Evidence considered
- ClinVar classification: Pathogenic
- COSMIC somatic count: 2
Still missing
- No proband specificity score data were identified.
- No case-control enrichment data were identified.
Sources
PM6 No assumed or confirmed de novo observations were identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
PP1 No segregation data were identified showing this variant co-segregates with PTEN-related disease in affected family members, so PP1 was not assessed. Details ▾Hide ▴
BS2 No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified, so BS2 was not assessed. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BS2.
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
Still missing
- No qualifying homozygous observations were identified.
Sources
BS3 No well-established functional study showing no damaging effect for this variant was identified. The PTEN saturation mutagenesis phosphatase dataset cited for BS3 is indexed for missense variants and does not apply to this frameshift variant. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BS3.
Evidence considered
- Mighell et al. PTEN functional dataset is indexed for missense variants.
Still missing
- No benign functional assay data were identified for this variant.
Sources
cspec ↗vcep_m_m_c_2
BS4 No data were identified showing lack of segregation in affected family members, so BS4 was not assessed. Details ▾Hide ▴
BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with different pathogenic PTEN variants, so BP2 was not assessed. Details ▾Hide ▴
BP5 No alternate highly penetrant molecular diagnosis with non-overlapping phenotype was identified, so BP5 was not assessed. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BP5.
Still missing
- No alternate molecular explanation was identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
PM4 N/APM4 is reserved for in-frame insertions or deletions and stop-loss variants. This variant is a frameshift, so PM4 is not applicable. Details ▾Hide ▴
PM5 N/APM5 applies to missense variants at a residue with a different pathogenic missense change. This frameshift variant does not meet that variant type requirement, so PM5 is not applicable. Details ▾Hide ▴
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a frameshift, so PP2 is not applicable. Details ▾Hide ▴
PP3 N/APTEN PP3 is specified for missense variants with REVEL greater than 0.7 or for splicing variants with concordant splicing predictions. This frameshift variant is not being interpreted as a missense or splice consensus variant, so PP3 is not applicable. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 PP3.
Evidence considered
- Variant consequence: frameshift
- SpliceAI max delta score: 0.06
Sources
PP4 N/APP4 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP4 N/APTEN BP4 is specified for missense variants with REVEL less than 0.5 or for splicing variants with concordant benign splicing predictions. This frameshift variant is not being interpreted as a missense or intronic/synonymous splicing variant, so BP4 is not applicable. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BP4.
Evidence considered
- Variant consequence: frameshift
- SpliceAI max delta score: 0.06
Sources
BP6 N/ABP6 is not applicable in the PTEN Expert Panel specification. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or deep intronic variants with no predicted splicing impact. This variant is a coding frameshift, so BP7 is not applicable. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BP7.
Evidence considered
- Variant consequence: frameshift
- SpliceAI max delta score: 0.06
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.743del
- Protein (HGVS p.)
- NP_000305.3:p.(Pro248LeufsTer8)
- GRCh38
- chr10:87957959 AC>A
- GRCh37
- chr10:89717716 AC>A
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/APTEN PP3 is specified for missense variants with REVEL greater than 0.7 or for splicing variants with concordant splicing predictions. This frameshift variant is not being interpreted as a missense or splice consensus variant, so PP3 is not applicable. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 PP3.
Evidence considered
- Variant consequence: frameshift
- SpliceAI max delta score: 0.06
Sources
BP4 N/APTEN BP4 is specified for missense variants with REVEL less than 0.5 or for splicing variants with concordant benign splicing predictions. This frameshift variant is not being interpreted as a missense or intronic/synonymous splicing variant, so BP4 is not applicable. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BP4.
Evidence considered
- Variant consequence: frameshift
- SpliceAI max delta score: 0.06
Sources
BP7 N/ABP7 applies to synonymous or deep intronic variants with no predicted splicing impact. This variant is a coding frameshift, so BP7 is not applicable. Details ▾Hide ▴
Rule
PTEN CSPEC v3.2.0 BP7.
Evidence considered
- Variant consequence: frameshift
- SpliceAI max delta score: 0.06
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
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/2674370/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89717716-AC-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87957959-AC-A?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.743d…
- OncoKB ↗www.oncokb.org/gene/PTEN/P248Lfs*8
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=117196755
- 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 (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
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 previously been reported in somatic cancers (COSMIC; COSV109436597, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.