About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.322C>G, p.(Leu108Val)
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: 2
Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below the PTEN PM2 threshold of 0.001% and supports rarity.
PP2Supporting
PP2 · supporting
This is a missense variant in PTEN, a gene for which the PTEN Expert Panel retains PP2 for missense variation as a disease mechanism with a low rate of benign missense variation.
Benign criteria applied · 1
BS3Supporting
BS3 · supporting
In the PTEN saturation mutagenesis phosphatase assay accepted by the PTEN Expert Panel, p.(Leu108Val) had a high-confidence cumulative fitness score of 1.160568514, which is above the BS3 threshold of >0 and supports no damaging effect on protein function.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP2 supporting, BS3 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
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
0.000 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 ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
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 · 6 not met · 10 not assessed · 9 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.322C>G (p.Leu108Val) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which supports rarity below the PTEN PM2 threshold of 0.001%.
In the PTEN saturation mutagenesis phosphatase assay accepted by the PTEN Expert Panel, p.Leu108Val had a high-confidence cumulative fitness score of 1.160568514, which is above the BS3 threshold of >0 and well above the PS3_Moderate damaging threshold of ≤-1.11, supporting no damaging effect on protein function.
Computational evidence is indeterminate overall: REVEL is 0.514, which is between the PTEN BP4 cutoff of <0.5 and PP3 cutoff of >0.7; BayesDel is 0.180271; and SpliceAI predicts no splice impact with a maximum delta score of 0.00.
No criteria match.
Met · 3
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below the PTEN PM2 threshold of 0.001% and supports rarity. Details ▾Hide ▴
Rule
PTEN PM2_Supporting applies when allele frequency is <0.001%, with subpopulation constraint <0.002% if multiple alleles are present.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- gnomAD-Canada absent
- PM2 threshold <0.001%
Sources
PP2 SupportingThis is a missense variant in PTEN, a gene for which the PTEN Expert Panel retains PP2 for missense variation as a disease mechanism with a low rate of benign missense variation. Details ▾Hide ▴
Rule
Missense variant in a gene with low benign missense variation and missense as a common disease mechanism.
Evidence considered
- Variant is missense
- PTEN CSPEC includes PP2
Sources
BS3 SupportingIn the PTEN saturation mutagenesis phosphatase assay accepted by the PTEN Expert Panel, p.(Leu108Val) had a high-confidence cumulative fitness score of 1.160568514, which is above the BS3 threshold of >0 and supports no damaging effect on protein function. Details ▾Hide ▴
Rule
PTEN BS3_Supporting applies when Mighell et al. 2018 phosphatase activity score is >0.
Evidence considered
- Table S2 variant L108V / Leu108Val
- Cum_score 1.160568514
- High_conf true
- BS3 threshold >0
Sources
Not met · 6 · evaluated, threshold not reached
PS3 In the PTEN saturation mutagenesis phosphatase assay accepted by the PTEN Expert Panel, p.(Leu108Val) had a high-confidence cumulative fitness score of 1.160568514, which is above the damaging threshold for PS3_Moderate of ≤-1.11 and does not support a damaging functional effect. Details ▾Hide ▴
Rule
PTEN PS3_Moderate requires phosphatase activity score ≤ -1.11 in Mighell et al. 2018.
Evidence considered
- Table S2 variant L108V / Leu108Val
- Cum_score 1.160568514
- High_conf true
- PS3_Moderate threshold <= -1.11
Sources
PM1 Residue Leu108 is outside the PTEN Expert Panel PM1 catalytic motif ranges 90-94, 123-130, and 166-168, and the available hotspot review did not provide a confirmed hotspot call at this residue. Details ▾Hide ▴
Rule
PTEN PM1 is limited to residues in catalytic motifs 90-94, 123-130, and 166-168.
Evidence considered
- PM1 motif ranges 90-94
- 123-130
- 166-168
- Variant residue 108
- Hotspot review uncertain
Sources
PP3 Computational evidence does not meet the PTEN PP3 threshold for missense variants: REVEL is 0.514, which is below the required >0.7 threshold. SpliceAI predicts no splice impact with a maximum delta score of 0.00, and BayesDel is 0.180271 but does not overcome the PTEN-specific REVEL rule. Details ▾Hide ▴
Rule
PTEN PP3 for missense variants requires REVEL > 0.7.
Evidence considered
- REVEL 0.514
- PP3 threshold >0.7
- SpliceAI max delta 0.00
- BayesDel 0.180271
Sources
BA1 This variant is absent from population databases and does not meet the PTEN BA1 threshold of >0.056%. Details ▾Hide ▴
Rule
PTEN BA1 requires filtering allele frequency >0.056%.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- gnomAD-Canada absent
- BA1 threshold >0.056%
Sources
BS1 This variant is absent from population databases and does not meet the PTEN BS1 thresholds of 0.00043%-0.0043% for supporting or 0.0043%-0.056% for strong evidence. Details ▾Hide ▴
Rule
PTEN BS1 uses allele-frequency ranges above rarity but below BA1.
Evidence considered
- gnomAD v2.1 absent
- gnomAD v4.1 absent
- gnomAD-Canada absent
- BS1 supporting threshold 0.00043%-0.0043%
- BS1 strong threshold 0.0043%-0.056%
Sources
BP4 Computational evidence does not meet the PTEN BP4 threshold for missense variants because REVEL is 0.514, which is above the benign cutoff of <0.5. SpliceAI predicts no splice impact with a maximum delta score of 0.00, but the PTEN missense BP4 rule is based on REVEL. Details ▾Hide ▴
Rule
PTEN BP4 for missense variants requires REVEL < 0.5.
Evidence considered
- REVEL 0.514
- BP4 threshold <0.5
- SpliceAI max delta 0.00
Sources
Not assessed · 10 · no assessment recorded
PS1 No validated previously established pathogenic variant producing the same amino acid change was identified in the available evidence, so PS1 was not assessed. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- No same-amino-acid pathogenic comparator documented in the reviewed materials
Still missing
- Direct same-amino-acid comparator review would be needed to exclude or support PS1.
PS2 No confirmed de novo observation with maternity and paternity established was identified for this variant. Details ▾Hide ▴
Rule
De novo occurrence with confirmed maternity and paternity in an affected individual.
Evidence considered
- ClinVar query returned no result
Still missing
- Case-level parental testing and phenotype details were not available.
Sources
PS4 No affected-proband count, specificity score, or case-control enrichment data were identified for this variant. Details ▾Hide ▴
Rule
Requires PTEN-specific proband specificity scoring or significant enrichment in affected individuals.
Evidence considered
- Variant absent from ClinVar
- Variant not reported in COSMIC
Still missing
- Published case observations or formal enrichment data were not available.
Sources
PM5 No validated pathogenic or likely pathogenic missense comparator at the same residue was established from the available evidence, so PM5 was not assessed. Details ▾Hide ▴
Rule
Requires a different pathogenic or likely pathogenic missense change at the same residue, with the queried variant having an equal or more severe BLOSUM62 score.
Evidence considered
- No usable same-residue comparator documented in reviewed materials
Still missing
- Direct review of same-residue PTEN missense comparators would be needed to support or exclude PM5.
Sources
pm5_candidatescspec ↗
PM6 No assumed de novo observation without parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Requires assumed de novo occurrence in an affected individual under PTEN-specific thresholds.
Evidence considered
- ClinVar query returned no result
Still missing
- Case-level de novo wording and phenotype details were not available.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
Requires co-segregation with disease in informative meioses under PTEN-specific thresholds.
Evidence considered
- No ClinVar submissions or linked family data
Still missing
- Pedigree-level informative meioses were not available.
Sources
BS2 No healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous observation was identified for this variant. Details ▾Hide ▴
Rule
Requires homozygous observations in healthy or unaffected individuals under PTEN-specific rules.
Evidence considered
- Variant absent from reviewed population databases
Still missing
- Unaffected homozygous observations were not available.
Sources
BS4 No lack-of-segregation data were identified for this variant. Details ▾Hide ▴
Rule
Requires lack of segregation in one or more families under PTEN-specific thresholds.
Evidence considered
- No ClinVar submissions or linked family data
Still missing
- Family segregation data were not available.
Sources
BP2 No in trans, in cis, or phase-unknown observation with another pathogenic or likely pathogenic PTEN variant was identified for this variant. Details ▾Hide ▴
Rule
Requires defined co-occurrence with pathogenic or likely pathogenic PTEN variants.
Evidence considered
- No ClinVar submissions or co-occurrence data
Still missing
- Phase and co-occurrence data were not available.
Sources
BP5 No alternate molecular explanation with non-overlapping phenotype information was identified for this variant. Details ▾Hide ▴
Rule
Requires an alternate highly penetrant molecular basis for disease with no phenotype overlap with PTEN.
Evidence considered
- No alternate molecular diagnosis documented in reviewed materials
Still missing
- Case-level alternate-diagnosis information was not available.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Leu108Val), and does not fall within the PTEN null-variant categories used for PVS1. Details ▾Hide ▴
Rule
PTEN PVS1 decision tree applies to null variants, not this missense change.
Evidence considered
- NM_000314.8:c.322C>G encodes p.(Leu108Val)
- PTEN PVS1 decision tree is for null variants
- generic PVS1 scaffold marked variant_bucket other
Sources
PM3 VCEPPM3 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
PM4 N/AThis variant does not cause a protein length change, in-frame insertion/deletion, or stop-loss event, so PM4 does not apply. Details ▾Hide ▴
Rule
PTEN PM4 applies to in-frame insertions/deletions affecting specified regions or stop-loss variants.
Evidence considered
- Variant is missense p.(Leu108Val)
Sources
PP4 VCEPPP4 is not applicable in the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
BP6 VCEPBP6 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
BP7 N/AThis variant is missense rather than synonymous or qualifying intronic, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN BP7 applies to synonymous or qualifying intronic variants with no predicted splice impact.
Evidence considered
- Variant is missense p.(Leu108Val)
- SpliceAI max delta 0.00
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.322C>G
- Protein (HGVS p.)
- NP_000305.3:p.(Leu108Val)
- GRCh38
- chr10:87933081 C>G
- GRCh37
- chr10:89692838 C>G
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
- 0.514
- BayesDel
- 0.180
How the predictions were used
PP3 Computational evidence does not meet the PTEN PP3 threshold for missense variants: REVEL is 0.514, which is below the required >0.7 threshold. SpliceAI predicts no splice impact with a maximum delta score of 0.00, and BayesDel is 0.180271 but does not overcome the PTEN-specific REVEL rule. Details ▾Hide ▴
Rule
PTEN PP3 for missense variants requires REVEL > 0.7.
Evidence considered
- REVEL 0.514
- PP3 threshold >0.7
- SpliceAI max delta 0.00
- BayesDel 0.180271
Sources
BP4 Computational evidence does not meet the PTEN BP4 threshold for missense variants because REVEL is 0.514, which is above the benign cutoff of <0.5. SpliceAI predicts no splice impact with a maximum delta score of 0.00, but the PTEN missense BP4 rule is based on REVEL. Details ▾Hide ▴
Rule
PTEN BP4 for missense variants requires REVEL < 0.5.
Evidence considered
- REVEL 0.514
- BP4 threshold <0.5
- SpliceAI max delta 0.00
Sources
BP7 N/AThis variant is missense rather than synonymous or qualifying intronic, so BP7 does not apply. Details ▾Hide ▴
Rule
PTEN BP7 applies to synonymous or qualifying intronic variants with no predicted splice impact.
Evidence considered
- Variant is missense p.(Leu108Val)
- SpliceAI max delta 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.514. BayesDel score = 0.180271.
1 paper record 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
-
PMID 25527629 ↗Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.No paper-specific finding is recorded.
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 0.000
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.322C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692838-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933081-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87933081-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.322C…
- OncoKB ↗www.oncokb.org/gene/PTEN/L108V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTEN+c.322C%3EG
- 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 = 0.00). REVEL score = 0.514. BayesDel score = 0.180271.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
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.