About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.263A>G, p.(Tyr88Cys)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Moderate
PS3 · moderate
In a published PTEN multiplex phosphatase assay, p.Tyr88Cys showed a cumulative functional score of -1.228, which is below the PTEN Expert Panel PS3_Moderate threshold of -1.11. This supports a damaging effect on PTEN function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the PTEN Expert Panel PM2_Supporting threshold of 0.001% and supports rarity in the general population.
PP2Supporting
PP2 · supporting
This is a missense variant in PTEN, a gene for which the PTEN Expert Panel permits PP2 because benign missense variation is relatively low and missense variants are a recognized disease mechanism. This supports PP2 at supporting strength.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious effect. REVEL is 0.927, which is above the PTEN Expert Panel PP3 threshold of 0.7 for missense variants; BayesDel is also in a deleterious range at 0.567202. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.03, supporting a protein-impact rather than splice-impact interpretation.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 moderate, PM2 supporting, PP2 supporting, PP3 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.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
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
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: 4 met · 9 not met · 7 not assessed · 8 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.263A>G (p.Tyr88Cys; p.Y88C) variant has been observed in somatic cancers in COSMIC (11 occurrences) and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting the PTEN Expert Panel PM2_Supporting threshold.
In a published PTEN multiplex phosphatase assay, p.Tyr88Cys had a cumulative functional score of -1.228, which is below the PTEN Expert Panel PS3_Moderate threshold of -1.11 and supports a damaging effect on PTEN function.
Computational evidence supports a deleterious effect, with REVEL 0.927 above the PTEN Expert Panel PP3 threshold of 0.7 and BayesDel 0.567202, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.03.
No criteria match.
Met · 4
PS3 ModerateIn a published PTEN multiplex phosphatase assay, p.Tyr88Cys showed a cumulative functional score of -1.228, which is below the PTEN Expert Panel PS3_Moderate threshold of -1.11. This supports a damaging effect on PTEN function. Details ▾Hide ▴
Rule
Phosphatase activity <= -1.11 per Mighell et al. 2018.
Evidence considered
- Mighell et al. functional assay
- Cum_score -1.228158575
- High confidence measurement
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1. Its observed population frequency is therefore below the PTEN Expert Panel PM2_Supporting threshold of 0.001% and supports rarity in the general population. Details ▾Hide ▴
Rule
Absent or below 0.001% allele frequency in a large population database.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
Sources
PP2 SupportingThis is a missense variant in PTEN, a gene for which the PTEN Expert Panel permits PP2 because benign missense variation is relatively low and missense variants are a recognized disease mechanism. This supports PP2 at supporting strength. 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 VCEP includes PP2 as applicable
Sources
PP3 SupportingComputational evidence supports a deleterious effect. REVEL is 0.927, which is above the PTEN Expert Panel PP3 threshold of 0.7 for missense variants; BayesDel is also in a deleterious range at 0.567202. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.03, supporting a protein-impact rather than splice-impact interpretation. Details ▾Hide ▴
Rule
Missense variants: REVEL score > 0.7.
Evidence considered
- REVEL 0.927
- BayesDel 0.567202
- SpliceAI max delta 0.03
Sources
Not met · 9 · evaluated, threshold not reached
PVS1 This missense variant does not fall into the PTEN PVS1 null-variant categories. Available PTEN-specific and generic PVS1 guidance indicates that c.263A>G (p.Tyr88Cys) is not a nonsense, frameshift, or canonical splice-site variant, so PVS1 is not applied. Details ▾Hide ▴
Rule
Use PTEN PVS1 decision tree; not applicable to this missense variant.
Evidence considered
- PTEN germline loss of function is an established disease mechanism
- Variant is a missense substitution outside the default PVS1 variant buckets
Sources
PS1 No previously established pathogenic PTEN variant producing the same amino acid change was identified. Available ClinVar evidence does not support PS1 for p.Tyr88Cys. Details ▾Hide ▴
PM1 p.Tyr88Cys is not within the PTEN catalytic motif residues defined by the Expert Panel for PM1 (residues 90-94, 123-130, and 166-168), and no statistically significant hotspot was identified from the available review. Available evidence does not support PM1. Details ▾Hide ▴
Rule
Located in a mutational hot spot and/or critical, well-established functional domain.
Evidence considered
- Residue 88 is outside PTEN PM1 catalytic motifs
- No hotspot row identified
Still missing
- Hotspot review was flagged for human review even though no hotspot was identified.
Sources
PM5 No different missense change at PTEN Tyr88 established as pathogenic or likely pathogenic was identified in the available ClinVar review. Available evidence does not support PM5. Details ▾Hide ▴
Rule
Different pathogenic or likely pathogenic missense change at the same residue.
Evidence considered
- Available ClinVar review did not identify a pathogenic or likely pathogenic alternative missense change at Tyr88
Still missing
- Broader codon-level curation outside currently retrieved sources could be reviewed if needed.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the PTEN Expert Panel BA1 threshold of 0.056%. BA1 is not met. Details ▾Hide ▴
Rule
Filtering allele frequency >0.056%.
Evidence considered
- Absent from gnomAD
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its frequency is below the PTEN Expert Panel BS1 thresholds of 0.00043% for supporting and 0.0043% for strong evidence. BS1 is not met. Details ▾Hide ▴
Rule
Allele frequency above PTEN BS1 thresholds.
Evidence considered
- Absent from gnomAD
Sources
BS2 No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified. Available evidence does not support BS2. Details ▾Hide ▴
Rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual.
Evidence considered
- Variant absent from gnomAD
- No homozygous unaffected observations identified
Still missing
- No healthy homozygous observations were identified.
Sources
BS3 Available functional evidence does not show retained PTEN function. In the published multiplex phosphatase assay, p.Tyr88Cys had a damaging score of -1.228 rather than a score above 0 required for BS3_Supporting, so BS3 is not met. Details ▾Hide ▴
Rule
Phosphatase activity >0 for BS3_Supporting.
Evidence considered
- Cum_score -1.228158575
- High confidence measurement
Sources
BP4 Computational evidence does not support a benign interpretation. REVEL is 0.927, which is above rather than below the PTEN Expert Panel BP4 missense threshold of 0.5. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, the missense prediction profile does not support BP4. Details ▾Hide ▴
Rule
Missense variants: REVEL score < 0.5.
Evidence considered
- REVEL 0.927
- SpliceAI max delta 0.03
Sources
Not assessed · 7 · no assessment recorded
PS2 No confirmed de novo observation with maternity and paternity testing was identified, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
PS4 This variant has been observed in somatic cancers, but no germline case-count, specificity-score, or case-control evidence was identified to support PS4 under the PTEN Expert Panel rules. Details ▾Hide ▴
Rule
Increased prevalence in affected individuals or PTEN-specific proband specificity scoring.
Evidence considered
- COSMIC somatic count 11
- No ClinVar germline record identified
Still missing
- No PTEN hamartoma tumor syndrome specificity score was identified.
- No affected-case enrichment analysis was identified.
Sources
PM6 No assumed de novo observation without confirmed parentage was identified, so PM6 cannot be assessed from the available evidence. Details ▾Hide ▴
PP1 No informative segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
BS4 No family study demonstrating lack of segregation was identified, so BS4 cannot be assessed from the available evidence. Details ▾Hide ▴
BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/phase unknown with the number of pathogenic variants required by the PTEN Expert Panel. BP2 cannot be assessed. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic variant or repeated cis/phase-unknown observations with pathogenic variants.
Evidence considered
- No co-occurrence evidence identified
Still missing
- No phase data were identified.
- No co-occurrence data with pathogenic PTEN variants were identified.
Sources
BP5 No alternate highly penetrant molecular explanation with non-overlapping clinical features was identified, so BP5 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease.
Evidence considered
- No alternate molecular diagnosis evidence identified
Still missing
- No phenotype and alternate-diagnosis data were identified.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable under the PTEN Expert Panel framework. Details ▾Hide ▴
PM4 N/APM4 is intended for in-frame insertions or deletions and stop-loss variants. This variant is a missense substitution, so PM4 is not applicable. Details ▾Hide ▴
PP4 N/APP4 is not applicable under the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4 scoring. Details ▾Hide ▴
PP5 N/APP5 is not applicable under the PTEN Expert Panel framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable under the PTEN Expert Panel framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable under the PTEN Expert Panel framework. Details ▾Hide ▴
BP6 N/ABP6 is not applicable under the PTEN Expert Panel framework. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or qualifying intronic variants without predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.263A>G
- Protein (HGVS p.)
- NP_000305.3:p.(Tyr88Cys)
- GRCh38
- chr10:87933022 A>G
- GRCh37
- chr10:89692779 A>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
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 SupportingComputational evidence supports a deleterious effect. REVEL is 0.927, which is above the PTEN Expert Panel PP3 threshold of 0.7 for missense variants; BayesDel is also in a deleterious range at 0.567202. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.03, supporting a protein-impact rather than splice-impact interpretation. Details ▾Hide ▴
Rule
Missense variants: REVEL score > 0.7.
Evidence considered
- REVEL 0.927
- BayesDel 0.567202
- SpliceAI max delta 0.03
Sources
BP4 Computational evidence does not support a benign interpretation. REVEL is 0.927, which is above rather than below the PTEN Expert Panel BP4 missense threshold of 0.5. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, the missense prediction profile does not support BP4. Details ▾Hide ▴
Rule
Missense variants: REVEL score < 0.5.
Evidence considered
- REVEL 0.927
- SpliceAI max delta 0.03
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants without predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.927. BayesDel score = 0.567202.
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.263A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692779-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933022-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.263A…
- OncoKB ↗www.oncokb.org/gene/PTEN/Y88C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=117170187
- 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 = 0.03). REVEL score = 0.927. BayesDel score = 0.567202.
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 does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64295989, n = 11 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.