About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.700_701del, p.(Arg234GlyfsTer8)
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. 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
Frameshift deletion (NM_000314.8:c.700_701del, p.Arg234GlyfsTer8) introduces a premature termination codon in exon 7 at approximately p.241, 5' to the p.D375 (c.1121) NMD threshold, and is predicted to undergo nonsense-mediated decay in the biologically relevant transcript NM_000314.8. PTEN loss of function is an established mechanism of PTEN hamartoma tumor syndrome; per the PTEN PVS1 decision tree this is assigned full-strength PVS1.
PM2Supporting
PM2 · supporting
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the PTEN VCEP PM2_Supporting threshold (allele frequency <0.001%).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ClinGen PTEN Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PTEN Version 3.2 v3.2 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.027 maximum delta
Recorded SpliceAI maximum delta score: 0.027. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64299636, n = 1 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, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 15 not met · 0 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
NM_000314.8:c.700_701del is a frameshift deletion in PTEN exon 7 producing p.Arg234GlyfsTer8, a premature termination codon predicted to undergo nonsense-mediated decay at or 5' to the p.D375 (c.1121) threshold, meeting PVS1 at very-strong strength per the PTEN expert panel decision tree.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength (<0.001% allele frequency).
The variant is absent from ClinVar; no functional, de novo, segregation, or case-level evidence is available to support or refute additional criteria.
Under the PTEN VCEP combination rules, a single PVS1 (very strong) criterion is sufficient for a Pathogenic classification (Rule 1, Condition 1).
No criteria match.
Met · 2
PVS1 Very strongFrameshift deletion (NM_000314.8:c.700_701del, p.Arg234GlyfsTer8) introduces a premature termination codon in exon 7 at approximately p.241, 5' to the p.D375 (c.1121) NMD threshold, and is predicted to undergo nonsense-mediated decay in the biologically relevant transcript NM_000314.8. PTEN loss of function is an established mechanism of PTEN hamartoma tumor syndrome; per the PTEN PVS1 decision tree this is assigned full-strength PVS1. Details ▾Hide ▴
Evidence considered
- Two-nucleotide frameshift deletion in exon 7 (c.635-801)
- Premature termination codon at p.241 (Arg234GlyfsTer8)
- 5' to p.D375 (c.1121) NMD cutoff
- Predicted to undergo NMD (PTC not in last exon
- transcript NM_000314.8 biologically relevant)
- PTEN LoF is an established autosomal dominant disease mechanism (PHTS)
Sources
PM2 SupportingThe variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the PTEN VCEP PM2_Supporting threshold (allele frequency <0.001%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 15 · evaluated, threshold not reached
PS1 No previously established pathogenic variant with the same amino acid change (p.Arg234GlyfsTer8) was identified, and the variant is absent from ClinVar, so PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no established pathogenic comparator with the same protein consequence
Sources
PS2 No de novo observation (with confirmed maternity and paternity) for this variant has been reported. Details ▾Hide ▴
Evidence considered
- No de novo reports identified for this variant
Still missing
- No family/de novo data available
PS3 No variant-specific experimental functional data exist. The PTEN VCEP PS3_Moderate path (Mighell et al. 2018 saturation mutagenesis, mmc2.xlsx) interrogates missense variants only and does not cover this frameshift. OncoKB's 'Likely Oncogenic / loss-of-function' annotation is a curated bioeffect prediction, not experimental functional evidence for this variant. Details ▾Hide ▴
Evidence considered
- Mighell et al. saturation assay is missense-only (Table S2 Type=missense)
- not applicable to a frameshift
- OncoKB Likely Oncogenic / likely loss-of-function bioeffect annotation (not experimental)
- Two retrieved gene-level functional papers do not test this specific variant
Still missing
- No experimental functional assay for this frameshift variant
Sources
vcep_mmc2oncokb ↗
PS4 No proband or affected-individual counts are available; the variant is absent from ClinVar and no case-control data exist. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no proband/specificity-score data
Still missing
- No case observations or case-control data
Sources
PM1 The frameshift occurs at Arg234 within the C2 domain; the PTEN VCEP-defined catalytic motifs (WPD loop 90-94, P-loop 123-130, TI-loop 166-168) lie N-terminal to this position and are preserved in the truncated protein. No mutational hotspot is present at this residue. Details ▾Hide ▴
Evidence considered
- PTEN VCEP PM1 defined to catalytic motifs 90-94
- 123-130
- 166-168 (NP_000305.3)
- all N-terminal to Arg234 and preserved
- No statistically significant hotspot at this residue (hotspots: not found)
Sources
PM6 No assumed de novo observation for this variant has been reported. Details ▾Hide ▴
Evidence considered
- No assumed de novo reports identified
Still missing
- No de novo data available
PP1 No co-segregation data with disease in affected family members are available for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data
Still missing
- No segregation data
PP3 PP3 (PTEN VCEP) requires REVEL >0.7 for missense variants or SpliceAI/VarSeak splicing concordance for splicing variants. REVEL is not computed for this frameshift, and SpliceAI predicts no splice impact (max delta score 0.027), so no computational evidence of a deleterious effect exists. Details ▾Hide ▴
Evidence considered
- REVEL/BayesDel not computed (not an SNV)
- SpliceAI max delta score 0.027 (no significant splice impact)
Sources
BA1 The variant is absent from gnomAD, far below the BA1 stand-alone threshold (filtering allele frequency >0.056%). Details ▾Hide ▴
BS1 The variant is absent from gnomAD, below the BS1 allele-frequency thresholds. Details ▾Hide ▴
BS2 No observation in the homozygous state in a healthy or PHTS-unaffected individual has been reported. Details ▾Hide ▴
BS3 No functional study demonstrating no damaging effect exists for this variant. The Mighell et al. saturation assay (BS3_Supporting path) is missense-only and does not apply to this frameshift. Details ▾Hide ▴
Evidence considered
- No benign functional data for this variant
- Mighell saturation assay is missense-only (not applicable)
Sources
vcep_mmc2
BS4 No lack-of-segregation data in affected family members are available. Details ▾Hide ▴
Evidence considered
- No segregation data
Still missing
- No segregation data
BP2 No observation in trans with a pathogenic/likely pathogenic PTEN variant, nor three observations in cis/unknown phase with different pathogenic PTEN variants, has been reported. Details ▾Hide ▴
Evidence considered
- No trans/cis phase data with a pathogenic PTEN variant
BP5 No case with an alternate molecular basis for disease has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No alternate-molecular-basis cases identified
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 VCEPRecessive-disorder criterion; PTEN hamartoma tumor syndrome is autosomal dominant and the PTEN VCEP marks PM3 not applicable. Details ▾Hide ▴
PM4 N/APM4 applies to in-frame insertions/deletions or stop-loss/protein-extension variants; this is an out-of-frame (frameshift) deletion that is captured by PVS1. Details ▾Hide ▴
Evidence considered
- Frameshift (out-of-frame) deletion
- not an in-frame indel or stop-loss
Sources
PM5 N/APM5 requires a missense change at a residue where a different missense change is established pathogenic; this is a frameshift deletion, not a missense substitution. Details ▾Hide ▴
Evidence considered
- Variant class is not missense-like
- no same-residue missense comparator applicable
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in a gene with a low rate of benign missense variation; this is a frameshift deletion. Details ▾Hide ▴
PP4 VCEPThe PTEN VCEP marks PP4 not applicable; phenotype specificity is incorporated into the PS4 specifications. Details ▾Hide ▴
PP5 VCEPThe PTEN VCEP marks PP5 'Not Applicable for this VCEP', and the variant is absent from ClinVar so there is no reputable-source pathogenic classification to credit. Details ▾Hide ▴
BP1 VCEPThe PTEN VCEP marks BP1 not applicable (missense variant in a gene where truncating variants cause disease is not applicable to PTEN). Details ▾Hide ▴
BP3 VCEPThe PTEN VCEP marks BP3 not applicable (in-frame indels in a repetitive region without known function). Details ▾Hide ▴
BP4 N/ABP4 (PTEN VCEP) applies to synonymous or intronic variants with no predicted splicing impact; it is not applicable to a frameshift deletion. Details ▾Hide ▴
BP6 VCEPThe PTEN VCEP marks BP6 'Not Applicable for this VCEP', and the variant is absent from ClinVar so there is no reputable-source benign classification to credit. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splicing impact; this is a frameshift deletion. Details ▾Hide ▴
PS5 N/APS5 is not a defined criterion in the PTEN VCEP v3.2 or in ACMG/AMP 2015; no rule applies. Details ▾Hide ▴
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.700_701del
- Protein (HGVS p.)
- NP_000305.3:p.(Arg234GlyfsTer8)
- GRCh38
- chr10:87957917 ACG>A
- GRCh37
- chr10:89717674 ACG>A
- COSMIC
- COSV64299636
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
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 (PTEN VCEP) requires REVEL >0.7 for missense variants or SpliceAI/VarSeak splicing concordance for splicing variants. REVEL is not computed for this frameshift, and SpliceAI predicts no splice impact (max delta score 0.027), so no computational evidence of a deleterious effect exists. Details ▾Hide ▴
Evidence considered
- REVEL/BayesDel not computed (not an SNV)
- SpliceAI max delta score 0.027 (no significant splice impact)
Sources
BP4 N/ABP4 (PTEN VCEP) applies to synonymous or intronic variants with no predicted splicing impact; it is not applicable to a frameshift deletion. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or intronic variants with no predicted splicing impact; this is a frameshift deletion. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
2 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
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PMID 11237521 ↗PTEN: life as a tumor suppressor.Review describing PTEN's role as a tumor suppressor, its mutational status in sporadic cancers, its function opposing PI3K/Akt signaling, and its domain structure. NM_000314.8:c.700_701del (p.Arg234GlyfsTer8) is not mentioned.Does not name this variant
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PMID 17218262 ↗Essential role for nuclear PTEN in maintaining chromosomal integrity.Reports a nuclear function for PTEN in chromosomal integrity, showing that C-terminal PTEN mutants disrupt centromere association and cause centromeric instability. The specific variant NM_000314.8:c.700_701del (p.Arg234GlyfsTer8) is not identified.Does not name this variant
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 0.027
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/?term=NM_000314.8%3Ac.700_701del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89717674-ACG-A?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87957917-ACG-A?dataset=…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87957917-ACG-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.700_…
- OncoKB ↗www.oncokb.org/gene/PTEN/R234Gfs*8
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139198187
- 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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; COSV64299636, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.