About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.898dup, p.(Ile300AsnfsTer3)
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 is predicted to create p.(Ile300AsnfsTer3) with a premature stop 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 through nonsense-mediated decay. Germline loss of function is an established disease mechanism for PTEN, so this evidence meets PVS1 at very strong strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. An observed allele frequency of 0 is below the PTEN PM2_Supporting threshold of 0.001% and is consistent with rarity in the general population.
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 · 2 not met · 11 not assessed · 13 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.898dup (p.Ile300AsnfsTer3; p.I300Nfs*3) variant has not been observed in COSMIC and has not been reported in ClinVar; OncoKB classifies it 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_Supporting threshold of 0.001% and is consistent with rarity in the general population.
This frameshift introduces a premature stop codon upstream of the PTEN-specific p.D375 (c.1121) threshold in NM_000314.8, which is consistent with predicted nonsense-mediated decay and supports PVS1 at very strong strength under the PTEN-specific decision tree.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, indicating that the primary predicted effect is protein truncation rather than altered splicing.
No criteria match.
Met · 2
PVS1 Very strongThis frameshift variant is predicted to create p.(Ile300AsnfsTer3) with a premature stop 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 through nonsense-mediated decay. Germline loss of function is an established disease mechanism for PTEN, so this evidence meets PVS1 at very strong strength. Details ▾Hide ▴
Rule
PTEN-specific PVS1 decision tree: frameshift or nonsense variants at or 5' to p.D375 (c.1121) in NM_000314.8 are assigned PVS1.
Evidence considered
- NM_000314.8:c.898dup causes NP_000305.3:p.(Ile300AsnfsTer3)
- PTEN PVS1 decision tree assigns full-strength PVS1 to frameshift variants at or 5' to p.D375 (c.1121)
- PTEN loss of function is an established germline disease mechanism
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. An observed allele frequency of 0 is below the PTEN PM2_Supporting threshold of 0.001% and is consistent with rarity in the general population. Details ▾Hide ▴
Rule
Absent or <0.001% in gnomAD; if multiple alleles are present within a subpopulation, that subpopulation frequency must be <0.002%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- PTEN PM2 applies at supporting strength for variants below 0.001%
Sources
Not met · 2 · evaluated, threshold not reached
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1. An observed allele frequency of 0 is below the PTEN BA1 threshold of 0.056%, so BA1 is not met. Details ▾Hide ▴
Rule
gnomAD filtering allele frequency >0.056%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BA1 threshold for PTEN is >0.056%
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1. An observed allele frequency of 0 is below the PTEN BS1_Supporting lower threshold of 0.00043% and below the BS1_Strong threshold range of 0.0043% to 0.056%, so BS1 is not met. Details ▾Hide ▴
Rule
BS1_Supporting: 0.00043% to <0.0043%; BS1_Strong: 0.0043% to 0.056%.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- BS1 thresholds for PTEN start at 0.00043%
Sources
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified showing that this variant produces the same amino acid change as a previously established pathogenic PTEN variant or the same nucleotide change as a known pathogenic splicing variant. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant, regardless of nucleotide change.
Evidence considered
- ClinVar search returned no record for this variant
Still missing
- A curated comparison against previously established pathogenic variants causing the same amino acid or splice outcome was not identified.
Sources
PS2 No confirmed de novo observation in an affected individual was identified for this variant. Details ▾Hide ▴
Rule
Confirmed de novo occurrence in a patient with the disease and no family history.
Evidence considered
- No de novo evidence was identified in the reviewed materials
Still missing
- Parental testing and family history data were not available.
Sources
PS3 No well-established variant-specific functional study was identified for this frameshift variant. The PTEN saturation mutagenesis phosphatase assay cited by the PTEN framework is for missense variants and does not provide a directly applicable result for this change. Details ▾Hide ▴
Rule
Well-established functional studies supportive of a damaging effect on the gene or gene product.
Evidence considered
- PTEN Mighell assay guidance is restricted to missense variants
Still missing
- Variant-specific functional data were not identified.
Sources
cspec ↗vcep_mmc2
PS4 No proband count, phenotype specificity score, or case-control enrichment data were identified for this variant, so increased prevalence in affected individuals could not be established. Details ▾Hide ▴
Rule
Increased prevalence in affected individuals or PTEN phenotype specificity score meeting PS4 thresholds.
Evidence considered
- ClinVar search returned no record for this variant
Still missing
- Published affected proband observations and phenotype specificity data were not identified.
Sources
PM6 No assumed de novo observation was identified for this variant. Details ▾Hide ▴
Rule
Assumed de novo occurrence in a proband with the disease and no family history.
Evidence considered
- No de novo evidence was identified in the reviewed materials
Still missing
- Family history and parental testing data were not available.
Sources
PP1 No segregation data were identified for this variant, so co-segregation with PTEN-related disease could not be evaluated. Details ▾Hide ▴
Rule
Co-segregation with disease in multiple affected family members with defined meiosis thresholds.
Evidence considered
- No segregation evidence was identified in the reviewed materials
Still missing
- Family segregation information was not available.
Sources
BS2 No observation of this variant in healthy or PTEN hamartoma tumor syndrome-unaffected homozygous individuals was identified. Details ▾Hide ▴
Rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual.
Evidence considered
- No BS2-qualifying observations were identified in the reviewed materials
Still missing
- Data on unaffected homozygous observations were not identified.
Sources
BS3 No well-established functional study showing no damaging effect was identified for this variant. The PTEN phosphatase activity framework cited for BS3 applies to missense variants and does not provide a directly applicable benign result for this frameshift change. Details ▾Hide ▴
Rule
Well-established functional studies showing no damaging effect on protein function or no splicing impact.
Evidence considered
- PTEN Mighell assay guidance is restricted to missense variants
Still missing
- Variant-specific benign functional data were not identified.
Sources
cspec ↗vcep_mmc2
BS4 No lack-of-segregation data were identified for this variant in affected family members. Details ▾Hide ▴
Rule
Lack of segregation in affected members of one or more families.
Evidence considered
- No BS4-qualifying family data were identified
Still missing
- Family segregation data were not available.
Sources
BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or repeated cis/phase-unknown observations with different pathogenic PTEN variants. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic/likely pathogenic PTEN variant or at least three cis/phase-unknown observations with different pathogenic PTEN variants.
Evidence considered
- No BP2-qualifying phase observations were identified
Still missing
- Phase and second-variant data were not available.
Sources
BP5 No alternate highly penetrant molecular diagnosis with non-overlapping clinical features was identified for this case, so BP5 could not be evaluated. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease and no clinical overlap with PTEN-related disease.
Evidence considered
- No BP5-qualifying alternate diagnosis was identified
Still missing
- Case-level phenotype and alternate molecular diagnosis data were not available.
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 N/APM1 is defined in the PTEN specification for variants affecting catalytic motif residues 90-94, 123-130, or 166-168. This frameshift affects codon 300, outside those PTEN catalytic motifs. Details ▾Hide ▴
Rule
Located in a PTEN catalytic motif: residues 90-94, 123-130, or 166-168.
Evidence considered
- Protein change is p.(Ile300AsnfsTer3)
- PTEN PM1 motifs are residues 90-94
- 123-130
- and 166-168
Sources
PM3 N/APM3 is marked not applicable in the PTEN expert specification. Details ▾Hide ▴
Rule
Not applicable in PTEN CSPEC.
Evidence considered
- PTEN CSPEC lists PM3 as not applicable
Sources
PM4 N/APM4 is intended for in-frame insertions or deletions and stop-loss variants. This variant is a frameshift truncating change, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length change due to in-frame insertion/deletion in a non-repeat region or stop-loss variant.
Evidence considered
- Variant consequence is frameshift
- not in-frame indel or stop-loss
Sources
PM5 N/APM5 applies to missense changes at a residue where a different pathogenic missense change has been observed. This variant is a frameshift, not a missense substitution. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- Protein consequence is frameshift
Sources
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. This variant is a frameshift and therefore PP2 does not apply. Details ▾Hide ▴
Rule
Missense variant in a gene with a low rate of benign missense variation and where missense is a common disease mechanism.
Evidence considered
- Protein consequence is frameshift
Sources
PP3 N/APP3 is specified for missense prediction or splicing prediction concordance. This variant is a non-canonical frameshift change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so PP3 is not the relevant evidence path for this variant. Details ▾Hide ▴
Rule
Computational evidence supporting deleterious effect for missense variants or concordant splice prediction for splicing variants.
Evidence considered
- SpliceAI max delta score = 0.01
- Variant is not a missense or canonical splice-site change
Sources
PP4 N/APP4 is marked not applicable in the PTEN expert specification. Details ▾Hide ▴
Rule
Not applicable in PTEN CSPEC.
Evidence considered
- PTEN CSPEC lists PP4 as not applicable
Sources
PP5 N/APP5 is marked not applicable in the PTEN expert specification. Details ▾Hide ▴
Rule
Not applicable in PTEN CSPEC.
Evidence considered
- PTEN CSPEC lists PP5 as not applicable
Sources
BP1 N/ABP1 is marked not applicable in the PTEN expert specification. Details ▾Hide ▴
Rule
Not applicable in PTEN CSPEC.
Evidence considered
- PTEN CSPEC lists BP1 as not applicable
Sources
BP3 N/ABP3 is marked not applicable in the PTEN expert specification. Details ▾Hide ▴
Rule
Not applicable in PTEN CSPEC.
Evidence considered
- PTEN CSPEC lists BP3 as not applicable
Sources
BP4 N/ABP4 is specified for missense prediction or concordant splice prediction showing no impact. This variant is a frameshift, and although SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, that does not offset the truncating consequence, so BP4 does not apply. Details ▾Hide ▴
Rule
Computational evidence suggesting no impact for missense variants or concordant no-impact splice prediction for splicing variants.
Evidence considered
- SpliceAI max delta score = 0.01
- Variant is a frameshift rather than a missense or intronic splice-prediction case
Sources
BP6 N/ABP6 is marked not applicable in the PTEN expert specification. Details ▾Hide ▴
Rule
Not applicable in PTEN CSPEC.
Evidence considered
- PTEN CSPEC lists BP6 as not applicable
Sources
BP7 N/ABP7 applies to synonymous or appropriately distal intronic variants with no predicted splice impact. This variant is a coding frameshift change, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Variant is a coding frameshift
- SpliceAI max delta score = 0.01
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.898dup
- Protein (HGVS p.)
- NP_000305.3:p.(Ile300AsnfsTer3)
- GRCh38
- chr10:87960987 G>GA
- GRCh37
- chr10:89720744 G>GA
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/APP3 is specified for missense prediction or splicing prediction concordance. This variant is a non-canonical frameshift change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so PP3 is not the relevant evidence path for this variant. Details ▾Hide ▴
Rule
Computational evidence supporting deleterious effect for missense variants or concordant splice prediction for splicing variants.
Evidence considered
- SpliceAI max delta score = 0.01
- Variant is not a missense or canonical splice-site change
Sources
BP4 N/ABP4 is specified for missense prediction or concordant splice prediction showing no impact. This variant is a frameshift, and although SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, that does not offset the truncating consequence, so BP4 does not apply. Details ▾Hide ▴
Rule
Computational evidence suggesting no impact for missense variants or concordant no-impact splice prediction for splicing variants.
Evidence considered
- SpliceAI max delta score = 0.01
- Variant is a frameshift rather than a missense or intronic splice-prediction case
Sources
BP7 N/ABP7 applies to synonymous or appropriately distal intronic variants with no predicted splice impact. This variant is a coding frameshift change, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Variant is a coding frameshift
- SpliceAI max delta score = 0.01
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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/?term=NM_000314.8%3Ac.898dupA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89720744-G-GA?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87960987-G-GA?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.898d…
- OncoKB ↗www.oncokb.org/gene/PTEN/I300Nfs*3
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.898dup
- 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 is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.