About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.927_937delinsT, p.(Asp310ArgfsTer4)
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
NM_000314.8:c.927_937delinsT is a frameshift variant predicted to result in a premature termination codon at p.Asp310ArgfsTer4 (p.313). Per the PTEN-specific PVS1 decision tree using transcript NM_000314.8, the stop codon occurs at position 313, which is 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay. The exon is present in the biologically-relevant transcript NM_000314.8. PVS1 is assigned at very strong strength.
PM2Supporting
PM2 · supporting
NM_000314.8:c.927_937delinsT is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per the PTEN VCEP, PM2 is applied at supporting strength when a variant is absent or present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population.
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
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. 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 · 14 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.927_937delinsT (p.Asp310ArgfsTer4) is a frameshift variant in exon 8 of PTEN, resulting in a premature termination codon at position 313. Per the PTEN-specific PVS1 decision tree, the stop codon lies 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay in the biologically-relevant transcript NM_000314.8. PVS1 is applied at very strong strength.
The variant is absent from all population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (0 alleles). Per the PTEN VCEP, PM2 is applied at supporting strength for variants absent from large sequenced populations.
This variant has not been reported in ClinVar and is absent from the somatic COSMIC database. No proband observations, co-segregation data, de novo reports, or functional studies were identified for this specific variant.
SpliceAI predicts no significant splicing impact (max delta score = 0.04), consistent with the variant's mechanism operating through protein truncation rather than aberrant splicing.
No criteria match.
Met · 2
PVS1 Very strongNM_000314.8:c.927_937delinsT is a frameshift variant predicted to result in a premature termination codon at p.Asp310ArgfsTer4 (p.313). Per the PTEN-specific PVS1 decision tree using transcript NM_000314.8, the stop codon occurs at position 313, which is 5' to the p.D375 (c.1121) NMD threshold, and the variant is predicted to undergo nonsense-mediated decay. The exon is present in the biologically-relevant transcript NM_000314.8. PVS1 is assigned at very strong strength. Details ▾Hide ▴
Evidence considered
- Frameshift variant creates premature stop at p.313
- 5' to p.D375 (c.1121) NMD threshold
- Exon 8 is present in biologically-relevant transcript NM_000314.8
- PTEN PVS1 decision tree assigns PVS1 (very strong) for nonsense/frameshift variants with stop codon at or 5' to p.D375
Sources
vcep_pvs1_decisiontree_ptenpvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_000314.8:c.927_937delinsT is absent from all population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per the PTEN VCEP, PM2 is applied at supporting strength when a variant is absent or present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- Absent from gnomAD v4.1 (0 alleles)
- Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
Not met · 14 · evaluated, threshold not reached
PS2 No de novo observation (confirmed or assumed) has been identified for NM_000314.8:c.927_937delinsT in the available evidence. PS2 requires a de novo occurrence in a patient with disease and no family history. Details ▾Hide ▴
Still missing
- No de novo data available for this variant
PS3 No variant-specific functional data is available for NM_000314.8:c.927_937delinsT. The PTEN VCEP specifies PS3 evidence from splicing assays, Mighell et al. 2018 phosphatase activity (missense-specific), or in vitro cellular assays. This frameshift variant is not a missense change and cannot be evaluated by the Mighell phosphatase assay. Neither of the two reviewed publications (PMID:11237521, PMID:17218262) reports experimental functional data for this variant. Details ▾Hide ▴
Still missing
- No functional studies testing this specific frameshift variant
PS4 No proband count or phenotype specificity score data is available for NM_000314.8:c.927_937delinsT. The PTEN VCEP requires proband counts with specificity scores to apply PS4 at any strength level. The variant is absent from ClinVar and no case-level observations were identified in the literature. Details ▾Hide ▴
Still missing
- No proband or case-control data available
PM1 The PTEN VCEP defines PM1 for variants located in catalytic motifs: WPD loop (residues 90-94), P-loop (residues 123-130), and TI-loop (residues 166-168) of NP_000305.3. The variant p.Asp310ArgfsTer4 begins at position 310, which lies far C-terminal to all three defined catalytic motifs. The variant does not reside in a mutational hotspot as defined by cancerhotspots.org. Details ▾Hide ▴
Evidence considered
- Position 310 is C-terminal to catalytic motifs (90-94
- 123-130
- 166-168)
- Not located in a statistically significant hotspot per cancerhotspots.org
PM6 No assumed or confirmed de novo observation has been identified for NM_000314.8:c.927_937delinsT. The PTEN VCEP requires at minimum one assumed de novo occurrence in a proband with disease and no family history to apply PM6 at moderate strength. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No co-segregation data is available for NM_000314.8:c.927_937delinsT. The PTEN VCEP requires at minimum 3-4 meioses to apply PP1 at supporting strength. No family studies were identified in the literature. Details ▾Hide ▴
Still missing
- No co-segregation or family data available
BA1 The PTEN VCEP defines BA1 for variants with gnomAD filtering allele frequency >0.00056 (0.056%). NM_000314.8:c.927_937delinsT is absent from all gnomAD populations (v2.1, v4.1, Canada). BA1 is not met. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD
- AF = 0
- well below BA1 threshold of >0.00056
Sources
BS1 The PTEN VCEP defines BS1 at strong strength for gnomAD filtering AF from 0.000043 to 0.00056, and at supporting strength for AF from 0.0000043 to 0.000043. NM_000314.8:c.927_937delinsT is absent from gnomAD (AF = 0). BS1 is not met. Details ▾Hide ▴
Evidence considered
- Variant is absent from gnomAD
- AF = 0
- below BS1 thresholds
Sources
BS2 The PTEN VCEP defines BS2 for a variant observed in the homozygous state in a healthy or PHTS-unaffected individual. NM_000314.8:c.927_937delinsT is absent from all population databases with no homozygous observations. No clinical reports of homozygous or healthy adult carriers were identified. Details ▾Hide ▴
Still missing
- No homozygous or healthy carrier data available
BS3 No well-established in vitro or in vivo functional studies demonstrate a lack of damaging effect for NM_000314.8:c.927_937delinsT. The PTEN VCEP BS3_Supporting rule references the Mighell et al. 2018 phosphatase assay (missense-specific), which does not apply to this frameshift variant. No splicing assay demonstrating no impact is available (SpliceAI max delta = 0.04 confirms no predicted splice effect, but BS3 requires experimental functional data, not in silico prediction alone). Details ▾Hide ▴
Still missing
- No functional studies demonstrating benign effect for this variant
BS4 The PTEN VCEP requires lack of segregation in affected members of two or more families for BS4 at strong strength, or one family for supporting strength. No segregation data is available for NM_000314.8:c.927_937delinsT. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 The PTEN VCEP defines BP2 for a variant observed in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis/phase unknown with different P/LP PTEN variants. No such observations are available for NM_000314.8:c.927_937delinsT. Details ▾Hide ▴
Still missing
- No phase data or co-occurrence observations available
BP4 The PTEN VCEP defines BP4 for synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak predict no splicing impact, or for missense variants with REVEL <0.5. NM_000314.8:c.927_937delinsT is a frameshift variant whose pathogenic mechanism operates through protein truncation and nonsense-mediated decay, not through altered splicing. While SpliceAI predicts no splice impact (max delta = 0.04), BP4 is designed for variants where splicing is the primary concern. The frameshift's established deleterious mechanism through PVS1 does not support application of BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04 does not predict splicing impact
- but BP4 inapplicable to frameshift truncating mechanism
Sources
BP5 The PTEN VCEP defines BP5 for a variant found in a case with an alternate molecular basis for disease, requiring at least two such cases with the alternate gene being highly penetrant and no phenotypic overlap with PTEN. No such cases have been identified for NM_000314.8:c.927_937delinsT. Details ▾Hide ▴
Still missing
- No cases with alternate molecular basis identified
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to variants causing the same amino acid change as a previously established pathogenic variant, or a different nucleotide substitution at the same position as a pathogenic splicing variant. This is a frameshift indel (NM_000314.8:c.927_937delinsT), not a single amino acid substitution or nucleotide substitution at a splice site. PS1 is not applicable to frameshift variants. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThe PTEN VCEP specifies PM4 for in-frame insertions or deletions impacting at least one residue in a catalytic motif, or for variants causing protein extension (stop-loss). NM_000314.8:c.927_937delinsT is a frameshift (out-of-frame) variant, not an in-frame deletion/insertion and not a stop-loss variant. PM4 is not applicable to frameshift variants under the PTEN VCEP. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AThe PTEN VCEP defines PM5 for a missense change at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic, with a BLOSUM62 score requirement. NM_000314.8:c.927_937delinsT is a frameshift indel, not a missense variant. The pm5_candidates analysis confirmed this variant is not eligible for classic same-residue missense PM5. Details ▾Hide ▴
Evidence considered
- Variant class is frameshift
- not missense
- PM5 framework does not apply
Sources
pm5_candidates
PP2 N/AThe PTEN VCEP defines PP2 as a missense variant in a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. NM_000314.8:c.927_937delinsT is a frameshift indel, not a missense variant. PP2 is not applicable to non-missense variants under the PTEN VCEP. Details ▾Hide ▴
No further detail was recorded.
PP3 N/AThe PTEN VCEP defines PP3 for missense variants with REVEL score >0.7 or splicing variants with concordant SpliceAI and VarSeak predictions. NM_000314.8:c.927_937delinsT is a frameshift indel. REVEL and BayesDel scores are not available for indels. SpliceAI max delta score is 0.04, indicating no significant splice impact. The variant's pathogenicity is assessed through the PVS1 framework rather than in silico prediction algorithms designed for missense and splice variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04 (no significant splicing impact)
- REVEL/BayesDel not applicable to indel variants
Sources
PP4 VCEPThe ClinGen PTEN Expert Panel determined PP4 is not applicable for this VCEP. Phenotype specificity has been incorporated into the rule specifications for PS4. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use under the PTEN VCEP framework. Details ▾Hide ▴
Sources
BP1 VCEPThe ClinGen PTEN Expert Panel has determined that BP1 is not applicable to PTEN. Per the VCEP: 'This rule is not applicable to PTEN.' Details ▾Hide ▴
Sources
BP3 VCEPThe ClinGen PTEN Expert Panel has determined that BP3 is not applicable to PTEN. Per the VCEP: 'This rule is not applicable to PTEN.' Details ▾Hide ▴
Sources
BP6 VCEPBP6 is designated as Not Applicable for this VCEP by the ClinGen Sequence Variant Interpretation VCEP Review Committee. This criterion is not for use under the PTEN VCEP framework. Details ▾Hide ▴
Sources
BP7 N/AThe PTEN VCEP defines BP7 for synonymous or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site. NM_000314.8:c.927_937delinsT is a frameshift coding indel, not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not defined in the ClinGen PTEN Expert Panel specifications (Version 3.2). This criterion does not appear in the VCEP criteria set. The variant is a frameshift indel, and the generic PS5 criterion (novel missense change at a residue with another pathogenic missense) is also inapplicable to non-missense variants. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.927_937delinsT
- Protein (HGVS p.)
- NP_000305.3:p.(Asp310ArgfsTer4)
- GRCh38
- chr10:87961019 AGATAATGACA>T
- GRCh37
- chr10:89720776 AGATAATGACA>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
BP4 The PTEN VCEP defines BP4 for synonymous or intronic variants where SpliceAI (0-0.2) and VarSeak predict no splicing impact, or for missense variants with REVEL <0.5. NM_000314.8:c.927_937delinsT is a frameshift variant whose pathogenic mechanism operates through protein truncation and nonsense-mediated decay, not through altered splicing. While SpliceAI predicts no splice impact (max delta = 0.04), BP4 is designed for variants where splicing is the primary concern. The frameshift's established deleterious mechanism through PVS1 does not support application of BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04 does not predict splicing impact
- but BP4 inapplicable to frameshift truncating mechanism
Sources
PP3 N/AThe PTEN VCEP defines PP3 for missense variants with REVEL score >0.7 or splicing variants with concordant SpliceAI and VarSeak predictions. NM_000314.8:c.927_937delinsT is a frameshift indel. REVEL and BayesDel scores are not available for indels. SpliceAI max delta score is 0.04, indicating no significant splice impact. The variant's pathogenicity is assessed through the PVS1 framework rather than in silico prediction algorithms designed for missense and splice variants. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.04 (no significant splicing impact)
- REVEL/BayesDel not applicable to indel variants
Sources
BP7 N/AThe PTEN VCEP defines BP7 for synonymous or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site. NM_000314.8:c.927_937delinsT is a frameshift coding indel, not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
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 biology as a tumor suppressor, including its role in the PI3K/AKT pathway and association with Cowden syndrome and sporadic cancers. NM_000314.8:c.927_937delinsT was not identified in this publication.Does not name this variant
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PMID 17218262 ↗Essential role for nuclear PTEN in maintaining chromosomal integrity.Demonstrates a nuclear function for PTEN in maintaining chromosomal integrity through centromere localization and interaction with CENP-C. The study characterizes PTEN.C124S (phosphatase-dead) and PTEN.R189X (C-terminal truncation) mutants in the context of centromeric instability and DNA repair, but does not investigate NM_000314.8:c.927_937delinsT or the p.Asp310ArgfsTer4 frameshift.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 0.040
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.927_937delinsT
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89720776-AGATAATGACA-T?dat…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87961019-AGATAATGACA-T?…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87961019-AGATAATGACA-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.927_…
- OncoKB ↗www.oncokb.org/gene/PTEN/D310Rfs*4
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.927_937delinsT
- 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 = 0.04).
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.