About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.951_952del, p.(Leu318TyrfsTer6)
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 variant NM_000314.8:c.951_952del introduces a premature termination codon at p.(Leu318TyrfsTer6), located at or 5' to p.D375 (c.1121) in biologically-relevant transcript NM_000314.8. The stop codon occurs ~55 nt upstream of the last exon-exon junction (exon 8/9 at c.1026/1027) and is predicted to undergo nonsense-mediated decay. Per PTEN VCEP PVS1 decision tree, this satisfies PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
Variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Per PTEN VCEP specification, PM2 is applied at supporting strength for variants with allele frequency < 0.00001 (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
0.020 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
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
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, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 15 not met · 0 not assessed · 11 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.951_952del is a frameshift deletion in exon 8 of PTEN resulting in a premature termination codon at p.(Leu318TyrfsTer6), located 5' of the p.D375 threshold and predicted to undergo nonsense-mediated decay, satisfying PVS1 at very strong strength per the PTEN VCEP decision tree.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, meeting PM2 at supporting strength per PTEN VCEP allele frequency threshold of < 0.001%.
No additional pathogenic or benign criteria are met. One very strong criterion (PVS1) and one supporting criterion (PM2) are applied. Per PTEN VCEP Rule 20, this combination of one very strong and one supporting criterion yields a classification of Likely Pathogenic.
No criteria match.
Met · 2
PVS1 Very strongFrameshift variant NM_000314.8:c.951_952del introduces a premature termination codon at p.(Leu318TyrfsTer6), located at or 5' to p.D375 (c.1121) in biologically-relevant transcript NM_000314.8. The stop codon occurs ~55 nt upstream of the last exon-exon junction (exon 8/9 at c.1026/1027) and is predicted to undergo nonsense-mediated decay. Per PTEN VCEP PVS1 decision tree, this satisfies PVS1 at very strong strength. Details ▾Hide ▴
Evidence considered
- Frameshift variant in exon 8 introduces premature stop at codon 324
- Stop codon is 5' of p.D375 (c.1121) positional threshold
- Predicted to undergo NMD: stop ~55 nt upstream of last exon-exon junction
- NM_000314.8 is the biologically-relevant MANE Select transcript
Sources
PM2 SupportingVariant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Per PTEN VCEP specification, PM2 is applied at supporting strength for variants with allele frequency < 0.00001 (0.001%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0)
- Absent from gnomAD v4.1 (AF = 0)
- Absent from gnomAD-Canada v1.0 (AF = 0)
Sources
Not met · 15 · evaluated, threshold not reached
PS1 No established pathogenic variant at the same amino acid position with the same change has been identified. This frameshift produces a novel premature termination, not matching a previously classified pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PS2 No de novo observation with confirmed parentage has been identified for this variant in any available data source. Details ▾Hide ▴
Still missing
- No patient-level data available to evaluate de novo status
PS3 No variant-specific functional data available. The PTEN VCEP-designated functional assay (Mighell et al. 2018, PMID:29706350 via mmc2.xlsx) covers missense variants only and does not include this frameshift deletion. No other functional studies testing this exact variant were identified in the literature. OncoKB annotation of Likely Loss-of-function is a curated assertion, not direct experimental evidence for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB annotates variant as Likely Oncogenic (Likely Loss-of-function) but this is a curated classification
- not experimental functional data
- VCEP mmc2.xlsx (Mighell et al. 2018) limited to missense variants only
Still missing
- No phosphatase activity data for frameshift variants in Mighell et al. assay
- No variant-specific functional studies identified in literature
Sources
PS4 No proband count or case-control data available. The variant is absent from ClinVar with zero submissions, providing no patient-level observations to evaluate PS4 specificity scores or odds ratios. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar with no submissions
Still missing
- No proband or case-control data available
Sources
PM1 The PTEN VCEP defines PM1 as limited to catalytic motif residues: 90-94 (WPD loop), 123-130 (P-loop), and 166-168 (TI-loop) per NP_000305.3. This variant is a frameshift at codon 318, located in the C2 domain well outside the VCEP-defined catalytic motifs. No statistically significant hotspot at this position was identified in cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- Variant at codon 318 is outside VCEP-defined catalytic motifs (90-94
- 123-130
- 166-168)
- Not located in a statistically significant cancer hotspot
Sources
PM6 No de novo observation (assumed or confirmed) has been identified for this variant in the available data. Details ▾Hide ▴
Still missing
- No patient-level data available to evaluate de novo occurrence
PP1 No co-segregation data available. No family studies reporting this variant with meiotic segregation counts were identified. Details ▾Hide ▴
Still missing
- No segregation data available
PP3 PP3 per PTEN VCEP applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL > 0.7). This is a frameshift deletion in the coding region. SpliceAI predicts no splice impact (max delta = 0.02), and REVEL/BayesDel scores are not available for non-SNV variants. No additional computational evidence supports a deleterious effect beyond what is already captured by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no predicted splicing impact)
- REVEL/BayesDel not applicable to deletion variants
- Frameshift deleteriousness already captured by PVS1
Sources
BA1 BA1 per PTEN VCEP requires a gnomAD filtering allele frequency > 0.00056 (0.056%). The variant is absent from all gnomAD populations (AF = 0). Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD v2.1 and v4.1
- AF does not approach BA1 threshold
Sources
BS1 BS1 per PTEN VCEP requires a gnomAD filtering allele frequency >= 0.0000043 (0.00043%). The variant is absent from all gnomAD populations (AF = 0). Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- AF does not meet BS1 threshold
Sources
BS2 BS2 requires observation of the variant in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations are reported in gnomAD or any other data source. Details ▾Hide ▴
Evidence considered
- No homozygous observations in gnomAD or other population databases
Sources
BS3 No functional studies demonstrating a benign effect have been identified. The PTEN VCEP-designated functional assay (Mighell et al. 2018, mmc2.xlsx) is limited to missense variants and does not include this frameshift deletion. Details ▾Hide ▴
Evidence considered
- VCEP mmc2.xlsx (Mighell et al. 2018) limited to missense variants
Still missing
- No functional benign-effect data for this variant
BS4 No segregation data demonstrating lack of segregation in affected family members are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No evidence that this variant has been observed in trans with a pathogenic or likely pathogenic PTEN variant, or in cis/unknown phase with at least three different pathogenic/likely pathogenic PTEN variants. Details ▾Hide ▴
Still missing
- No phase data available
BP5 No evidence that this variant has been found in cases with an alternate molecular basis for disease. PTEN VCEP requires at least two such cases with a highly penetrant alternate gene/disorder and no phenotypic overlap with PTEN. Details ▾Hide ▴
Still missing
- No cases with alternate molecular diagnosis identified
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/APM4 per PTEN VCEP applies to in-frame insertions or deletions impacting at least one catalytic motif residue, or variants causing protein extension. This variant is an out-of-frame (frameshift) deletion, not an in-frame deletion. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a missense change at an amino acid residue where a different missense change has been classified as pathogenic. This variant is a frameshift deletion (p.Leu318TyrfsTer6), not a missense substitution, and does not meet the requirement for same-residue missense comparison. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json confirms variant class is not missense-like
- PM5 not eligible
Sources
pm5_candidates
PP2 N/APP2 per PTEN VCEP applies specifically to missense variants in a gene with a low rate of benign missense variation. This variant is a frameshift deletion, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPPP4 is designated Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the PS4 rule specifications. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is designated Not Applicable by the PTEN VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is designated Not Applicable for PTEN by the VCEP. This rule (missense variant in a gene where primarily truncating variants cause disease) is not applicable to PTEN. Details ▾Hide ▴
Sources
BP3 VCEPBP3 is designated Not Applicable for PTEN by the VCEP. This rule (in-frame deletions/insertions in a repetitive region) is not applicable to PTEN. Details ▾Hide ▴
Sources
BP4 N/ABP4 per PTEN VCEP applies to synonymous or intronic variants where SpliceAI and VarSeak predict no splicing impact. This is a coding frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPBP6 is designated Not Applicable by the PTEN VCEP as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
BP7 N/ABP7 per PTEN VCEP applies to synonymous (silent) or intronic variants at or beyond +7/-21 with no predicted splicing impact. This is a coding frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not included in the PTEN VCEP specification (ClinGen PTEN Expert Panel v3.2). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.951_952del
- Protein (HGVS p.)
- NP_000305.3:p.(Leu318TyrfsTer6)
- GRCh38
- chr10:87961042 TAC>T
- GRCh37
- chr10:89720799 TAC>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
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 per PTEN VCEP applies to splicing variants (SpliceAI + VarSeak concordance) or missense variants (REVEL > 0.7). This is a frameshift deletion in the coding region. SpliceAI predicts no splice impact (max delta = 0.02), and REVEL/BayesDel scores are not available for non-SNV variants. No additional computational evidence supports a deleterious effect beyond what is already captured by PVS1. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.02 (no predicted splicing impact)
- REVEL/BayesDel not applicable to deletion variants
- Frameshift deleteriousness already captured by PVS1
Sources
BP4 N/ABP4 per PTEN VCEP applies to synonymous or intronic variants where SpliceAI and VarSeak predict no splicing impact. This is a coding frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 per PTEN VCEP applies to synonymous (silent) or intronic variants at or beyond +7/-21 with no predicted splicing impact. This is a coding frameshift deletion, not a synonymous or intronic variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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 article discussing PTEN discovery, mutational spectrum in sporadic cancers, role in Cowden disease and Bannayan-Zonana syndrome, PI3K/AKT pathway regulation, and functional domain architecture. NM_000314.8:c.951_952del was not identified in this review.Does not name this variant
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PMID 17218262 ↗Essential role for nuclear PTEN in maintaining chromosomal integrity.Functional study demonstrating nuclear PTEN localizes at centromeres and interacts with CENP-C to maintain chromosomal integrity. Characterizes PTEN mutants including C124S (phosphatase-dead) and R189X (C-terminal truncation found in Cowden syndrome). NM_000314.8:c.951_952del was not studied or mentioned.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 0.020
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.951_952del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89720799-TAC-T?dataset=gno…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87961042-TAC-T?dataset=…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87961042-TAC-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.951_…
- OncoKB ↗www.oncokb.org/gene/PTEN/L318Yfs*6
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.951_952del
- 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 = 0.02).
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.