About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.-361C>T, p.?
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BS1Supporting
BS1 · supporting
The gnomAD v4.1 filtering allele frequency is 6.24e-06, which falls within the PTEN BS1_Supporting range of 0.0000043 to 0.000043 and below the BS1 strong range of 0.000043 to 0.00056; therefore BS1 is met at supporting strength.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: BS1 supporting; no rule matched the adjudicated criteria.
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
6 / 492,096 alleles
gnomAD v4.1: 6 / 492,096 alleles. Recorded AF 1.21927e-05. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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 ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
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: 1 met · 4 not met · 12 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
The PTEN NM_000314.8:c.-361C>T (NP_000305.3:p.?) variant has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 but present in gnomAD v4.1 at 6/492096 alleles, with filtering allele frequency 6.24e-06; this is above the PTEN PM2 cutoff and within the PTEN BS1_supporting frequency range.
No criteria match.
Met · 1
BS1 SupportingThe gnomAD v4.1 filtering allele frequency is 6.24e-06, which falls within the PTEN BS1_Supporting range of 0.0000043 to 0.000043 and below the BS1 strong range of 0.000043 to 0.00056; therefore BS1 is met at supporting strength. Details ▾Hide ▴
Rule
BS1_Supporting
Evidence considered
- gnomAD v4.1 joint grpmax FAF is 6.24e-06.
Sources
Not met · 4 · evaluated, threshold not reached
PVS1 This 5'UTR variant does not fall into the PTEN PVS1 decision tree categories for nonsense, frameshift, canonical +/-1,2 splice, or exon-level loss-of-function variants, so PVS1 is not met. Details ▾Hide ▴
Rule
PTEN VCEP PVS1 decision tree
Evidence considered
- PTEN loss of function is an established disease mechanism in the PTEN VCEP framework.
- NM_000314.8:c.-361C>T was assessed as a non-null 'other' variant bucket outside generic PVS1 default categories.
Still missing
- No exact-variant RNA or other null-effect study was identified.
Sources
PM2 This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 1.21927e-05, with highest subpopulation AF 4.45315e-05, which is above the PTEN PM2 threshold of <0.00001 overall and <0.00002 within a subpopulation when multiple alleles are observed; therefore PM2 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Present in gnomAD v4.1 with 6/492096 alleles and highest subpopulation AF 4.45315e-05.
Sources
BA1 The gnomAD v4.1 filtering allele frequency for this variant is 6.24e-06, which is below the PTEN BA1 threshold of >0.00056, so BA1 is not met. Details ▾Hide ▴
BS2 No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 reports 0 homozygotes.
Still missing
- No healthy homozygous carrier evidence was found.
Sources
Not assessed · 12 · no assessment recorded
PS1 No previously established pathogenic variant causing the same amino acid change or an equivalent pathogenic splicing effect at this nucleotide was identified, so PS1 was not assessed. Details ▾Hide ▴
PS2 No confirmed de novo occurrence in an affected individual was identified, so PS2 was not assessed. Details ▾Hide ▴
PS3 No well-established functional study showing a damaging effect of this exact 5'UTR variant on PTEN splicing, transcript abundance, or gene function was identified, so PS3 was not assessed. Details ▾Hide ▴
Evidence considered
- The PTEN VCEP functional phosphatase assay resource is for missense variants and does not apply to this noncoding variant.
Still missing
- No exact-variant RNA
- promoter
- or expression assay result was identified.
Sources
cspec ↗vcep_mmc2
PS4 No enrichment data or counted affected probands meeting PTEN VCEP PS4 specifications were identified for this variant, so PS4 was not assessed. Details ▾Hide ▴
PM6 No presumed de novo occurrence without parental confirmation was identified, so PM6 was not assessed. Details ▾Hide ▴
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
PP3 The PTEN VCEP applies PP3 to concordant SpliceAI and VarSeak splicing predictions for synonymous or intronic variants, or to missense variants with REVEL >0.7. This 5'UTR variant is not missense, REVEL is unavailable, and no concordant PTEN VCEP splicing prediction result was available, so PP3 was not assessed. Details ▾Hide ▴
Evidence considered
- REVEL was not available for this variant.
- PTEN PP3 noncoding use requires concordant SpliceAI and VarSeak evidence.
Still missing
- No PTEN VCEP-compatible noncoding splicing prediction result set was identified.
Sources
BS3 No well-established study showing no damaging effect of this exact 5'UTR variant on PTEN function or splicing was identified, so BS3 was not assessed. Details ▾Hide ▴
Evidence considered
- The PTEN VCEP missense phosphatase assay resource does not apply to this noncoding variant.
Still missing
- No exact-variant benign functional assay was identified.
Sources
cspec ↗vcep_mmc2
BS4 No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
BP2 No observation of this variant in trans with a pathogenic PTEN variant, or at least three cis/phase-unknown observations with different pathogenic PTEN variants, was identified, so BP2 was not assessed. Details ▾Hide ▴
BP4 The PTEN VCEP applies BP4 to synonymous or intronic variants with concordant benign SpliceAI and VarSeak splicing predictions, or to missense variants with REVEL <0.5. This 5'UTR variant is not missense, REVEL is unavailable, and no concordant PTEN VCEP splicing prediction result was available, so BP4 was not assessed. Details ▾Hide ▴
Evidence considered
- REVEL was not available for this variant.
- PTEN BP4 noncoding use requires concordant SpliceAI and VarSeak evidence.
Still missing
- No PTEN VCEP-compatible benign noncoding splicing prediction result set was identified.
Sources
BP5 No alternate molecular diagnosis with non-overlapping phenotype was identified, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data were provided.
Still missing
- No case-level alternate diagnosis information was available.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PM1 N/AThis variant is in the 5'UTR and not in the PTEN catalytic motifs at residues 90-94, 123-130, or 166-168, so PM1 is not applicable. Details ▾Hide ▴
Evidence considered
- PTEN PM1 is restricted to defined catalytic motifs in the protein.
Sources
PM3 VCEPPM3 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
PM4 N/AThis variant does not cause an in-frame protein length change or stop-loss effect, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- NM_000314.8:c.-361C>T is a 5'UTR substitution with no protein length alteration.
Sources
PM5 N/APTEN uses classic same-residue missense PM5 logic, and this variant is not missense-like, so PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- PM5 candidate review found the variant was not eligible for classic same-residue missense PM5 evaluation.
Sources
cspec ↗pm5_candidates
PP2 N/APP2 is a missense criterion, and this variant is a 5'UTR substitution, so PP2 is not applicable. Details ▾Hide ▴
PP4 VCEPPP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP6 VCEPBP6 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, and this variant is a 5'UTR substitution, so BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.-361C>T
- Protein (HGVS p.)
- NP_000305.3:p.?
- GRCh38
- chr10:87864109 C>T
- GRCh37
- chr10:89623866 C>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
6 / 492,096 alleles
AF 1.22e-05 · 0 homozygotes · FAF 6.24e-06
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-05 · 6 / 492,096 alleles · 0 hom · FAF 6.2e-06
| Remaining individuals1 / 22,456 | 4.5e-05 |
| European (non-Finnish)5 / 279,178 | 1.8e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.21927e-05; MAF= 0.00122%, 6/492096 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.45315e-05; MAF= 0.00445%, 1/22456 alleles, homozygotes = 0); grpmax FAF= 6.24e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 The PTEN VCEP applies PP3 to concordant SpliceAI and VarSeak splicing predictions for synonymous or intronic variants, or to missense variants with REVEL >0.7. This 5'UTR variant is not missense, REVEL is unavailable, and no concordant PTEN VCEP splicing prediction result was available, so PP3 was not assessed. Details ▾Hide ▴
Evidence considered
- REVEL was not available for this variant.
- PTEN PP3 noncoding use requires concordant SpliceAI and VarSeak evidence.
Still missing
- No PTEN VCEP-compatible noncoding splicing prediction result set was identified.
Sources
BP4 The PTEN VCEP applies BP4 to synonymous or intronic variants with concordant benign SpliceAI and VarSeak splicing predictions, or to missense variants with REVEL <0.5. This 5'UTR variant is not missense, REVEL is unavailable, and no concordant PTEN VCEP splicing prediction result was available, so BP4 was not assessed. Details ▾Hide ▴
Evidence considered
- REVEL was not available for this variant.
- PTEN BP4 noncoding use requires concordant SpliceAI and VarSeak evidence.
Still missing
- No PTEN VCEP-compatible benign noncoding splicing prediction result set was identified.
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants, and this variant is a 5'UTR substitution, so BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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
6 / 492,096 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC 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.-361C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89623866-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87864109-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.-361…
- OncoKB ↗www.oncokb.org/gene/PTEN/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.-361C%3ET
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.21927e-05; MAF= 0.00122%, 6/492096 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 4.45315e-05; MAF= 0.00445%, 1/22456 alleles, homozygotes = 0); grpmax FAF= 6.24e-06.
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 = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).