About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.388_389insA, p.(Arg130GlnfsTer50)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
Frameshift insertion c.388_389insA produces a premature termination codon at p.Arg130GlnfsTer50 (p.179), which is 5' of the p.D375 (c.1121) threshold in the PTEN VCEP PVS1 decision tree. The variant is predicted to undergo nonsense-mediated decay. Assigned PVS1 (very strong) per ClinGen PTEN Expert Panel specifications v3.2.0.
PM1Moderate
PM1 · moderate
The variant disrupts codon 130 (p.Arg130), which lies within the PTEN VCEP-defined catalytic motif spanning residues 123-130 (NP_000305.3). This frameshift insertion removes the critical phosphatase catalytic domain function. Additionally, the residue lies within a statistically significant cancer hotspot (cancerhotspots.org).
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the PTEN VCEP PM2 threshold of allele frequency <0.00001 (0.001%). Per VCEP specification, PM2 is applied at supporting evidence level.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule3 (1 Pathogenic.Very Strong + 1 Pathogenic.Moderate + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM1 moderate, PM2 supporting; maps to 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
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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 lies 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: 3 met · 12 not met · 0 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
NM_000314.8:c.388_389insA is a frameshift insertion in PTEN exon 5 producing p.Arg130GlnfsTer50, predicted to undergo nonsense-mediated decay well 5' of the p.D375 threshold, meeting PVS1 (very strong) per the ClinGen PTEN Expert Panel PVS1 decision tree v3.2.0.
The variant disrupts codon 130 within the PTEN catalytic motif (residues 123-130, NP_000305.3), a critical functional domain, meeting PM1 (moderate) per PTEN VCEP specifications.
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level per PTEN VCEP allele frequency threshold of <0.00001 (0.001%).
No functional studies, case reports, de novo observations, or segregation data were identified for this variant in the reviewed literature.
Under the PTEN VCEP classification framework, PVS1 (very strong) plus one moderate criterion (PM1) meets Rule 10 for Likely Pathogenic classification.
No criteria match.
Met · 3
PVS1 Very strongFrameshift insertion c.388_389insA produces a premature termination codon at p.Arg130GlnfsTer50 (p.179), which is 5' of the p.D375 (c.1121) threshold in the PTEN VCEP PVS1 decision tree. The variant is predicted to undergo nonsense-mediated decay. Assigned PVS1 (very strong) per ClinGen PTEN Expert Panel specifications v3.2.0. Details ▾Hide ▴
Evidence considered
- Frameshift insertion in exon 5 generating a premature stop at codon 179
- well 5' of the p.D375 (c.1121) NMD threshold
- LoF mechanism established for PTEN per CSPEC/VCEP framework
- Transcript NM_000314.8 is the biologically-relevant MANE Select transcript
Sources
vcep_pvs1_decisiontree_ptenpvs1_gene_contextpvs1_variant_assessment
PM1 ModerateThe variant disrupts codon 130 (p.Arg130), which lies within the PTEN VCEP-defined catalytic motif spanning residues 123-130 (NP_000305.3). This frameshift insertion removes the critical phosphatase catalytic domain function. Additionally, the residue lies within a statistically significant cancer hotspot (cancerhotspots.org). Details ▾Hide ▴
Evidence considered
- Residue 130 is the terminal residue of the VCEP-defined catalytic motif 123-130 (NP_000305.3)
- Frameshift at this position completely disrupts the phosphatase catalytic core
- Residue is in a statistically significant cancer hotspot
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the PTEN VCEP PM2 threshold of allele frequency <0.00001 (0.001%). Per VCEP specification, PM2 is applied at supporting evidence level. 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 · 12 · evaluated, threshold not reached
PS2 No de novo observation with confirmed paternity and maternity has been identified for this variant in the available evidence. Details ▾Hide ▴
Still missing
- No parental testing data available for this variant
PS3 No variant-specific functional assay data is available for NM_000314.8:c.388_389insA. The PTEN VCEP-designated Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis assay (mmc2.xlsx) covers missense variants only and does not include frameshift variants. The two reviewed publications (PMID: 11237521, PMID: 17218262) discuss PTEN at the gene level and do not report functional data for this variant. Details ▾Hide ▴
Evidence considered
- No functional data for this frameshift variant in any reviewed source
- Mighell et al. 2018 assay is limited to missense variants per VCEP specification
Still missing
- No functional assay data available for this specific frameshift variant
PS4 No proband counts or case-control data are available for this variant. The variant is absent from ClinVar, and no case reports mentioning this variant were identified in the reviewed literature. Details ▾Hide ▴
Still missing
- No proband or case-control data available
PM6 No assumed de novo observation has been reported for this variant. No proband with disease and no family history is documented in the available evidence. Details ▾Hide ▴
Still missing
- No de novo observations reported
PP1 No co-segregation data are available for this variant. No families with multiple affected members have been reported. Details ▾Hide ▴
Still missing
- No segregation data available
BA1 The variant is absent from gnomAD (allele frequency 0). The PTEN VCEP BA1 threshold of >0.00056 (0.056%) filtering allele frequency is not met. Details ▾Hide ▴
BS1 The variant is absent from gnomAD. The PTEN VCEP BS1 thresholds (0.000043-0.00056 for strong, 0.0000043-0.000043 for supporting) are not met at zero allele frequency. Details ▾Hide ▴
Evidence considered
- gnomAD allele frequency = 0
- well below BS1 thresholds
Sources
BS2 No homozygous observation in a healthy or PHTS-unaffected individual has been reported for this variant. The variant is absent from gnomAD, and no clinical data support a homozygous healthy carrier. Details ▾Hide ▴
Still missing
- No homozygous observations reported
BS3 No well-established functional studies demonstrate a benign effect for this variant. The PTEN VCEP BS3 specifications apply to splicing assays (strong) or Mighell et al. 2018 phosphatase activity >0 (supporting), which is limited to missense variants and does not address this frameshift insertion. Details ▾Hide ▴
Evidence considered
- No functional data available for this frameshift variant
Still missing
- No benign functional evidence available
BS4 No lack-of-segregation data are available for this variant. No families with affected members lacking the variant have been reported. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No observation of this variant in trans with a pathogenic or likely pathogenic PTEN variant, and no observations in cis with different P/LP PTEN variants have been reported. Details ▾Hide ▴
Still missing
- No phase data with other PTEN variants available
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. The PTEN VCEP requires at least two such cases. Details ▾Hide ▴
Still missing
- No cases with alternate molecular basis identified
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to variants producing the same amino acid change as a known pathogenic variant. This is a frameshift insertion producing a novel reading frame with a premature termination codon; there is no applicable 'same amino acid change' comparator for a frameshift variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThe PTEN VCEP PM4 specification applies to in-frame insertions/deletions impacting catalytic motif residues and to stop-loss variants causing protein extension. This variant is a frameshift insertion, not an in-frame indel, and is appropriately addressed under PVS1 rather than PM4. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a missense change at an amino acid residue where a different pathogenic missense change has been seen. This variant is a frameshift insertion, not a missense substitution, and does not meet the residue-level missense comparator requirement. Details ▾Hide ▴
No further detail was recorded.
PP2 N/APP2 is specified for missense variants in genes with a low rate of benign missense variation. This variant is a frameshift insertion, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PP3 N/AThe PTEN VCEP PP3 specification applies REVEL score >0.7 for missense variants, or SpliceAI/VarSeak concordance for splicing variants. This is a frameshift insertion; REVEL and BayesDel scores are not available for insertion variants, and SpliceAI predicts no splice impact (max delta 0.01). No applicable in silico evidence can be assessed. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no predicted splice impact)
- REVEL/BayesDel not applicable for insertion variants
PP4 VCEPThe PTEN VCEP considers PP4 not applicable; phenotype specificity has been incorporated into the PS4 rule specifications. Details ▾Hide ▴
Sources
PP5 VCEPThe PTEN VCEP designates PP5 as not applicable per ClinGen SVI VCEP Review Committee recommendations. Details ▾Hide ▴
Sources
BP1 VCEPThe PTEN VCEP designates BP1 as not applicable to PTEN. Details ▾Hide ▴
Sources
BP3 VCEPBP3 is designated as not applicable by the PTEN VCEP. Details ▾Hide ▴
Sources
BP4 N/AThe PTEN VCEP BP4 applies to synonymous or intronic variants with concordant benign SpliceAI/VarSeak predictions, or missense variants with REVEL <0.5. This is a frameshift insertion; BP4 is not specified for frameshift variants, and the SpliceAI max delta of 0.01 is not informative for a coding frameshift. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (not relevant for frameshift coding variant)
BP6 VCEPThe PTEN VCEP designates BP6 as not applicable per ClinGen SVI VCEP Review Committee recommendations. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies to synonymous or intronic variants at or beyond +7/-21 with no predicted splice impact. This is a coding frameshift insertion and does not meet the variant type requirement. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a recognized ACMG/AMP criterion. The ACMG/AMP 2015 framework does not include PS5. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.388_389insA
- Protein (HGVS p.)
- NP_000305.3:p.(Arg130GlnfsTer50)
- GRCh38
- chr10:87933147 C>CA
- GRCh37
- chr10:89692904 C>CA
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 N/AThe PTEN VCEP PP3 specification applies REVEL score >0.7 for missense variants, or SpliceAI/VarSeak concordance for splicing variants. This is a frameshift insertion; REVEL and BayesDel scores are not available for insertion variants, and SpliceAI predicts no splice impact (max delta 0.01). No applicable in silico evidence can be assessed. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no predicted splice impact)
- REVEL/BayesDel not applicable for insertion variants
BP4 N/AThe PTEN VCEP BP4 applies to synonymous or intronic variants with concordant benign SpliceAI/VarSeak predictions, or missense variants with REVEL <0.5. This is a frameshift insertion; BP4 is not specified for frameshift variants, and the SpliceAI max delta of 0.01 is not informative for a coding frameshift. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (not relevant for frameshift coding variant)
BP7 N/ABP7 applies to synonymous or intronic variants at or beyond +7/-21 with no predicted splice impact. This is a coding frameshift insertion and does not meet the variant type requirement. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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 structure, function, and mutational spectrum in sporadic cancers and hamartoma syndromes. NM_000314.8:c.388_389insA was not identified in this paper.Does not name this variant
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PMID 17218262 ↗Essential role for nuclear PTEN in maintaining chromosomal integrity.Reports nuclear function of PTEN in maintaining chromosomal integrity via centromere interaction and Rad51 regulation. NM_000314.8:c.388_389insA was not identified in this paper.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 0.010
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.388_389insA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692904-C-CA?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933147-C-CA?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87933147-C-CA
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.388_…
- OncoKB ↗www.oncokb.org/gene/PTEN/R130Qfs*50
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.388_389insA
- 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 = 0.01).
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 lies in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant lies in a statistically significant hotspot.