About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.434T>G, p.(Phe145Cys)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of <0.00001 (0.001%) and consistent with an ultra-rare allele in population databases.
PP2Supporting
PP2 · supporting
This variant is a missense change in PTEN, a gene for which the PTEN VCEP allows PP2 because benign missense variation is relatively low and missense change is an established disease mechanism.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.861, which is above the PTEN PP3 threshold of >0.7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so the in silico concern is for protein effect rather than splicing.
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: 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 has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: PTEN, a lipid and protein phosphatase, is one of the most frequently mutated genes in cancer.
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: 3 met · 8 not met · 9 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.434T>G (p.Phe145Cys; p.F145C) variant has been observed once in somatic cancers in COSMIC and has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of 0.001% and supports PM2 at Supporting strength.
In the PTEN saturation mutagenesis phosphatase assay, p.Phe145Cys had a cumulative activity score of -0.669, which is above the PTEN PS3_Moderate cutoff of <= -1.11 and below the BS3 threshold of >0, so the current functional evidence does not independently meet PS3 or BS3.
Computational evidence supports a deleterious protein effect because the REVEL score is 0.861, above the PTEN PP3 threshold of >0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.
No criteria match.
Met · 3
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PTEN PM2 threshold of <0.00001 (0.001%) and consistent with an ultra-rare allele in population databases. Details ▾Hide ▴
Rule
PTEN PM2_Supporting: allele frequency <0.00001, with subpopulation requirement if multiple alleles are present.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- PTEN PM2 is applied at Supporting strength for alleles <0.00001.
Sources
PP2 SupportingThis variant is a missense change in PTEN, a gene for which the PTEN VCEP allows PP2 because benign missense variation is relatively low and missense change is an established disease mechanism. Details ▾Hide ▴
Rule
PTEN PP2: missense variant in a gene with low benign missense variation where missense is a common disease mechanism.
Evidence considered
- The variant is missense p.(Phe145Cys).
- PTEN VCEP specifies PP2 as applicable for missense variants.
Sources
PP3 SupportingComputational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.861, which is above the PTEN PP3 threshold of >0.7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so the in silico concern is for protein effect rather than splicing. Details ▾Hide ▴
Rule
PTEN PP3: missense variants with REVEL >0.7.
Evidence considered
- REVEL score 0.861.
- PTEN PP3 for missense variants uses REVEL >0.7.
- SpliceAI max delta score 0.01.
Sources
Not met · 8 · evaluated, threshold not reached
PS3 Functional testing from the PTEN saturation mutagenesis assay showed a cumulative phosphatase activity score of -0.669 for p.Phe145Cys, which is above the PTEN PS3_Moderate threshold of <= -1.11. No additional validated functional study showing splicing disruption or clearly damaging PTEN function was identified, so PS3 is not met. Details ▾Hide ▴
Rule
PTEN PS3_Moderate: phosphatase activity <= -1.11 in Mighell et al. 2018.
Evidence considered
- Mighell et al. Table S2 lists F145C with Cum_score -0.669136514 and High_conf false.
- PTEN VCEP applies PS3_Moderate at phosphatase activity <= -1.11.
Sources
PM1 This missense variant affects residue 145, which is outside the PTEN catalytic motif residues defined for PM1 (90-94, 123-130, and 166-168). Available evidence also does not show a confirmed statistically significant hotspot for this residue, so PM1 is not met. Details ▾Hide ▴
Rule
PTEN PM1 applies to catalytic motif residues 90-94, 123-130, and 166-168.
Evidence considered
- PTEN PM1 is restricted to residues in catalytic motifs 90-94
- 123-130
- and 166-168.
- Cancer Hotspots did not confirm a statistically significant hotspot at F145.
Sources
PM4 This variant is a missense substitution and does not cause an in-frame protein length change or stop-loss, so PM4 is not met. Details ▾Hide ▴
Rule
PTEN PM4 applies to in-frame insertions/deletions affecting specified residues or stop-loss variants.
Evidence considered
- The variant consequence is missense p.(Phe145Cys).
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not exceed the PTEN BA1 threshold of >0.00056 (0.056%). Details ▾Hide ▴
Rule
PTEN BA1: filtering allele frequency >0.00056.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD v2.1 and v4.1 and therefore does not reach the PTEN BS1 thresholds of 0.0000043 to 0.000043 for Supporting or 0.000043 to 0.00056 for Strong evidence. Details ▾Hide ▴
Rule
PTEN BS1_Supporting: 0.0000043 to 0.000043; BS1_Strong: 0.000043 to 0.00056.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS2 No observation of this variant in a healthy or PTEN-hamartoma-tumor-syndrome-unaffected homozygous individual was identified, so BS2 is not met. Details ▾Hide ▴
Rule
PTEN BS2 requires homozygous observation in a healthy or unaffected individual.
Evidence considered
- The variant is absent from gnomAD v2.1 and v4.1.
Sources
BS3 Available functional evidence does not show normal PTEN function. In the Mighell assay, the cumulative phosphatase activity score for p.Phe145Cys is -0.669, which is below the PTEN BS3_Supporting threshold of >0, so BS3 is not met. Details ▾Hide ▴
Rule
PTEN BS3_Supporting: phosphatase activity >0 in Mighell et al. 2018.
Evidence considered
- Mighell et al. Table S2 lists F145C with Cum_score -0.669136514.
- PTEN BS3_Supporting requires phosphatase activity >0.
Sources
BP4 Computational evidence does not support a benign protein effect for this missense variant because the REVEL score is 0.861, which is above the PTEN BP4 threshold of <0.5. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, the missense prediction does not support BP4. Details ▾Hide ▴
Rule
PTEN BP4: missense variants with REVEL <0.5.
Evidence considered
- REVEL score 0.861.
- PTEN BP4 for missense variants uses REVEL <0.5.
- SpliceAI max delta score 0.01.
Sources
Not assessed · 9 · no assessment recorded
PS1 No previously established pathogenic variant causing the same amino acid change was identified in the available evidence, so PS1 was not assessed. Details ▾Hide ▴
PS2 No de novo data were identified for this variant, so PS2 was not assessed. Details ▾Hide ▴
Evidence considered
- No family-based de novo evidence was available.
Still missing
- Parental testing or published proven de novo observations would be needed.
Sources
PS4 The available evidence does not provide germline proband counts, phenotype specificity scoring, or a case-control analysis showing enrichment in affected individuals, so PS4 was not assessed. Details ▾Hide ▴
PM5 No previously established pathogenic missense variant at residue Phe145 was identified in the available evidence, so PM5 was not assessed. Details ▾Hide ▴
PM6 No assumed de novo observations were identified for this variant, so PM6 was not assessed. Details ▾Hide ▴
Evidence considered
- No de novo case information was available.
Still missing
- Published or laboratory de novo observations without confirmed parentage would be needed.
Sources
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Evidence considered
- No family segregation evidence was available.
Still missing
- Family segregation data with informative meioses would be needed.
Sources
BS4 No lack-of-segregation evidence was identified for this variant, so BS4 was not assessed. Details ▾Hide ▴
Evidence considered
- No family segregation evidence was available.
Still missing
- Family studies showing lack of segregation in one or more families would be needed.
Sources
BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or in cis/unknown phase in at least three observations with different pathogenic PTEN variants, so BP2 was not assessed. Details ▾Hide ▴
Evidence considered
- No allelic phase data were available.
Still missing
- Phase information with pathogenic or likely pathogenic PTEN variants would be needed.
Sources
BP5 No evidence was identified that this variant was found in a case with a separate highly penetrant molecular diagnosis and a non-overlapping clinical history, so BP5 was not assessed. Details ▾Hide ▴
Evidence considered
- No alternate molecular diagnosis data were available.
Still missing
- Case-level molecular and phenotype data would be needed.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, p.(Phe145Cys), and does not fall into the PTEN null-variant categories used for PVS1 such as nonsense, frameshift, or canonical +/-1,2 splice variants. Details ▾Hide ▴
Rule
PTEN PVS1 decision tree applies to null/splice-disrupting variants, not this missense variant.
Evidence considered
- PTEN loss of function is an established disease mechanism in the PTEN VCEP framework.
- The variant-specific PVS1 scaffold states that this variant does not fit generic null-variant buckets.
Sources
PM3 N/APM3 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- PTEN VCEP marks PM3 as not applicable.
Sources
PP4 N/APP4 is not applicable in the PTEN VCEP framework because phenotype specificity is incorporated into PS4 specifications. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- PTEN VCEP marks PP4 as not applicable.
Sources
PP5 N/APP5 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- PTEN VCEP marks PP5 as not applicable.
Sources
BP1 N/ABP1 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- PTEN VCEP marks BP1 as not applicable.
Sources
BP3 N/ABP3 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- PTEN VCEP marks BP3 as not applicable.
Sources
BP6 N/ABP6 is not applicable in the PTEN VCEP framework. Details ▾Hide ▴
Rule
Not applicable for this VCEP.
Evidence considered
- PTEN VCEP marks BP6 as not applicable.
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants and is not applicable to this missense variant. Details ▾Hide ▴
Rule
PTEN BP7 applies to synonymous or intronic variants at or beyond +7/-21.
Evidence considered
- The variant consequence is missense p.(Phe145Cys).
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.434T>G
- Protein (HGVS p.)
- NP_000305.3:p.(Phe145Cys)
- GRCh38
- chr10:87933193 T>G
- GRCh37
- chr10:89692950 T>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 for this missense variant because the REVEL score is 0.861, which is above the PTEN PP3 threshold of >0.7. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so the in silico concern is for protein effect rather than splicing. Details ▾Hide ▴
Rule
PTEN PP3: missense variants with REVEL >0.7.
Evidence considered
- REVEL score 0.861.
- PTEN PP3 for missense variants uses REVEL >0.7.
- SpliceAI max delta score 0.01.
Sources
BP4 Computational evidence does not support a benign protein effect for this missense variant because the REVEL score is 0.861, which is above the PTEN BP4 threshold of <0.5. Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, the missense prediction does not support BP4. Details ▾Hide ▴
Rule
PTEN BP4: missense variants with REVEL <0.5.
Evidence considered
- REVEL score 0.861.
- PTEN BP4 for missense variants uses REVEL <0.5.
- SpliceAI max delta score 0.01.
Sources
BP7 N/ABP7 applies to synonymous or qualifying intronic variants and is not applicable to this missense variant. Details ▾Hide ▴
Rule
PTEN BP7 applies to synonymous or intronic variants at or beyond +7/-21.
Evidence considered
- The variant consequence is missense p.(Phe145Cys).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.861. BayesDel score = 0.334659.
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.434T%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692950-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933193-T-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.434T…
- OncoKB ↗www.oncokb.org/gene/PTEN/F145C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=117172580
- 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). REVEL score = 0.861. BayesDel score = 0.334659.
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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; COSV100909311, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.