About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.367C>G, p.(His123Asp)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely 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: 7
Benign evidence criteria: 0
Pathogenic criteria applied · 7
PS3Moderate
PS3 · moderate
In the PTEN saturation mutagenesis phosphatase assay, p.His123Asp had a cumulative fitness score of -4.3458 with a high-confidence result flag, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11 and supports a damaging effect on PTEN function.
PM1Moderate
PM1 · moderate
This missense variant affects codon 123, which lies within the PTEN catalytic motif spanning residues 123-130 defined by the PTEN Expert Panel as a critical functional region for PM1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) and supports rarity in population databases.
PM5Moderate
PM5 · moderate
A different missense change at the same residue, PTEN p.His123Arg, is established as pathogenic by expert panel review in ClinVar. The observed substitution p.His123Asp has a BLOSUM62 score of -1, which is equal to or more deleterious than the comparator p.His123Arg score of 0, meeting the PTEN Expert Panel PM5 rule.
PP2Supporting
PP2 · supporting
This is a missense variant in PTEN, a gene for which the PTEN Expert Panel permits PP2 because missense variation is a recognized disease mechanism and benign missense variation is comparatively constrained.
PP3Supporting
PP3 · supporting
REVEL is 0.98, which is above the PTEN Expert Panel PP3 threshold of >0.7 and supports a deleterious missense effect. BayesDel is also positive at 0.601229, while SpliceAI shows a low maximum delta score of 0.01, which does not suggest a splice effect.
PP5Supporting
PP5 · supporting
Expert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
Richards et.al., 2015 - Combining rules v3.2.0 criteria-combination framework: matched Rule13 (Pathogenic.Moderate >=3) with applied criteria: PS3 moderate, PM1 moderate, PM2 supporting, PM5 moderate, PP2 supporting, PP3 supporting, PP5 supporting; maps to Likely 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.
ClinVar submissions
4 reported laboratory submissions
3 Likely pathogenic · 1 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64294365, n = 3 times).
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: 7 met · 5 not met · 8 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.367C>G (p.His123Asp) variant has been observed in somatic cancers (COSMIC COSV64294365, n=3) and has been reported in ClinVar, including a pathogenic expert-panel classification.
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is below the PTEN Expert Panel PM2 threshold for population rarity.
In the PTEN saturation mutagenesis phosphatase assay, p.His123Asp showed a high-confidence damaging result with cumulative fitness score -4.3458, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11.
Computational evidence supports a deleterious effect, with REVEL 0.98 above the PTEN Expert Panel PP3 threshold of >0.7 and BayesDel 0.601229 positive, while SpliceAI max delta 0.01 does not suggest splice disruption.
This variant also affects a PTEN catalytic motif residue and a different missense change at the same codon has been established as pathogenic, supporting PM1 and PM5 under the PTEN specification.
No criteria match.
Met · 7
PS3 ModerateIn the PTEN saturation mutagenesis phosphatase assay, p.His123Asp had a cumulative fitness score of -4.3458 with a high-confidence result flag, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11 and supports a damaging effect on PTEN function. Details ▾Hide ▴
Rule
PTEN EP: apply PS3_Moderate when phosphatase activity score is <= -1.11 per Mighell et al. 2018.
Evidence considered
- mmc2 Table S2: H123D
- Cum_score -4.345802175
- High_conf true
Sources
PM1 ModerateThis missense variant affects codon 123, which lies within the PTEN catalytic motif spanning residues 123-130 defined by the PTEN Expert Panel as a critical functional region for PM1. Details ▾Hide ▴
Rule
Located in a mutational hot spot and/or critical and well-established functional domain; PTEN catalytic motifs include residues 90-94, 123-130, and 166-168.
Evidence considered
- PTEN EP catalytic motif includes residues 123-130
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, which is below the PTEN Expert Panel PM2 threshold of <0.00001 (0.001%) and supports rarity in population databases. Details ▾Hide ▴
Rule
PTEN EP: PM2_Supporting when allele frequency is <0.00001 and subpopulation criteria are satisfied.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- Absent from gnomAD-Canada v1.0
Sources
PM5 ModerateA different missense change at the same residue, PTEN p.His123Arg, is established as pathogenic by expert panel review in ClinVar. The observed substitution p.His123Asp has a BLOSUM62 score of -1, which is equal to or more deleterious than the comparator p.His123Arg score of 0, meeting the PTEN Expert Panel PM5 rule. Details ▾Hide ▴
Rule
Missense change at an amino acid residue where a different pathogenic or likely pathogenic missense change has been seen before, with BLOSUM62 score equal to or less than the known variant.
Evidence considered
- ClinVar VCV000007816 p.His123Arg reviewed by expert panel as pathogenic
- BLOSUM62 H->D = -1 and H->R = 0
Sources
PP2 SupportingThis is a missense variant in PTEN, a gene for which the PTEN Expert Panel permits PP2 because missense variation is a recognized disease mechanism and benign missense variation is comparatively constrained. Details ▾Hide ▴
Rule
Missense variant in a gene with low benign missense variation and where missense variants are a common mechanism of disease.
Evidence considered
- PTEN EP PP2 specification
Sources
PP3 SupportingREVEL is 0.98, which is above the PTEN Expert Panel PP3 threshold of >0.7 and supports a deleterious missense effect. BayesDel is also positive at 0.601229, while SpliceAI shows a low maximum delta score of 0.01, which does not suggest a splice effect. Details ▾Hide ▴
Rule
PTEN EP: PP3 for missense variants when REVEL score is >0.7.
Evidence considered
- REVEL 0.98
- BayesDel 0.601229
- SpliceAI max delta 0.01
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No evidence was identified that this nucleotide change produces the same amino acid substitution as a previously established pathogenic variant through a different DNA change. Details ▾Hide ▴
BA1 This variant is absent from population databases and does not meet the PTEN Expert Panel BA1 threshold of >0.00056 (0.056%). Details ▾Hide ▴
Rule
BA1 when filtering allele frequency is >0.00056.
Evidence considered
- Absent from gnomAD datasets
Sources
BS1 This variant is absent from population databases and does not meet the PTEN Expert Panel BS1 thresholds of 0.0000043 to 0.00056. Details ▾Hide ▴
Rule
BS1 when allele frequency is within the PTEN benign range.
Evidence considered
- Absent from gnomAD datasets
Sources
BS3 Available functional evidence does not show preserved PTEN function. Instead, the PTEN phosphatase assay showed a damaging result with cumulative fitness score -4.3458, so BS3 is not supported. Details ▾Hide ▴
Rule
BS3_Supporting for phosphatase activity >0 per Mighell et al. 2018.
Evidence considered
- mmc2 Table S2: damaging functional result for H123D
Sources
BP4 Computational evidence does not support a benign effect. REVEL is 0.98, which is above the PTEN Expert Panel benign threshold of <0.5 for missense variants. Details ▾Hide ▴
Rule
BP4 for missense variants when REVEL score is <0.5.
Evidence considered
- REVEL 0.98
Sources
cspec ↗revel
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with documented maternity and paternity confirmation was identified. Details ▾Hide ▴
Rule
De novo occurrence in a patient with the disease and no family history.
Evidence considered
- ClinVar literature trail reviewed for de novo leads
Still missing
- Confirmed de novo case data with phenotype and parental testing
Sources
PS4 This variant has been reported in ClinVar and in somatic cancer databases, but no case-control enrichment data or PTEN Expert Panel phenotype specificity score was identified to support PS4. Details ▾Hide ▴
Rule
Requires PTEN phenotype specificity scoring or significant enrichment in affected individuals versus controls.
Evidence considered
- ClinVar pathogenic expert-panel record
- COSMIC somatic count 3
Still missing
- Quantified proband data or case-control enrichment meeting PTEN PS4 thresholds
Sources
PM6 No assumed de novo occurrence with the required phenotype and family-history context was identified. Details ▾Hide ▴
Rule
Assumed de novo occurrence in a patient with the disease and no family history.
Evidence considered
- ClinVar literature trail reviewed for de novo leads
Still missing
- Documented assumed de novo case(s) meeting PTEN PM6 thresholds
Sources
PP1 No segregation data were identified to show co-segregation with disease across informative meioses. Details ▾Hide ▴
BS2 No homozygous observations in healthy or PTEN hamartoma tumor syndrome-unaffected individuals were identified. Details ▾Hide ▴
Rule
Observed in the homozygous state in a healthy or unaffected individual.
Evidence considered
- No homozygous population observations identified
Still missing
- Documented homozygous observations with unaffected status
Sources
BS4 No data were identified showing lack of segregation in one or more affected families. Details ▾Hide ▴
BP2 No phase data were identified showing this variant in trans with a pathogenic PTEN variant or recurrently in cis/phase unknown with pathogenic PTEN variants. Details ▾Hide ▴
BP5 No alternate highly penetrant molecular explanation with non-overlapping phenotype was identified to support BP5. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease and no phenotype overlap with PTEN.
Evidence considered
- No qualifying alternate-diagnosis evidence identified
Still missing
- Documented alternate molecular diagnosis with non-overlapping phenotype
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, canonical +/-1 or 2 splice, or exon-level loss-of-function event, so the PTEN-specific PVS1 decision tree does not apply. Details ▾Hide ▴
Rule
Use PTEN PVS1 decision tree for null/splice/CNV variants only.
Evidence considered
- NM_000314.8:c.367C>G predicts p.(His123Asp)
- PTEN PVS1 framework is limited to null/splice/CNV contexts
Sources
PM3 VCEPPM3 is not applicable in the PTEN Expert Panel framework for this disorder context. Details ▾Hide ▴
PM4 N/AThis variant does not cause an in-frame insertion, in-frame deletion, or stop-loss event, so PM4 does not apply. Details ▾Hide ▴
Rule
Applies to protein length changes due to in-frame indels or stop-loss variants.
Evidence considered
- Variant is a missense substitution
Sources
PP4 VCEPPP4 is not applicable in the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4 scoring. 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 is not a synonymous or qualifying deep intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Applies to synonymous or intronic variants at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Variant is missense
- SpliceAI max delta 0.01
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.367C>G
- Protein (HGVS p.)
- NP_000305.3:p.(His123Asp)
- GRCh38
- chr10:87933126 C>G
- GRCh37
- chr10:89692883 C>G
- ClinVar
- 428277
- COSMIC
- COSV64294365
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
- 0.980
- BayesDel
- 0.601
How the predictions were used
PP3 SupportingREVEL is 0.98, which is above the PTEN Expert Panel PP3 threshold of >0.7 and supports a deleterious missense effect. BayesDel is also positive at 0.601229, while SpliceAI shows a low maximum delta score of 0.01, which does not suggest a splice effect. Details ▾Hide ▴
Rule
PTEN EP: PP3 for missense variants when REVEL score is >0.7.
Evidence considered
- REVEL 0.98
- BayesDel 0.601229
- SpliceAI max delta 0.01
Sources
BP4 Computational evidence does not support a benign effect. REVEL is 0.98, which is above the PTEN Expert Panel benign threshold of <0.5 for missense variants. Details ▾Hide ▴
Rule
BP4 for missense variants when REVEL score is <0.5.
Evidence considered
- REVEL 0.98
Sources
cspec ↗revel
BP7 N/AThis is not a synonymous or qualifying deep intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Applies to synonymous or intronic variants at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Variant is missense
- SpliceAI max delta 0.01
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.98. BayesDel score = 0.601229.
7 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 11918710 ↗PTEN mutations in eight Spanish families and one Brazilian family with Cowden syndrome.Bussaglia E et al. · 2002No paper-specific finding is recorded.
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PMID 21828076 ↗A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes.Rodríguez-Escudero I et al. · 2011No paper-specific finding is recorded.
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PMID 10555148 ↗Crystal structure of the PTEN tumor suppressor: implications for its phosphoinositide phosphatase activity and membrane association.Lee JO et al. · 1999No paper-specific finding is recorded.
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PMID 10772829 ↗Cell cycle arrest by the PTEN tumor suppressor is target cell specific and may require protein phosphatase activity.Hlobilkova A et al. · 2000No paper-specific finding is recorded.
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PMID 16619501 ↗Tumour suppressor PTEN regulates cell cycle and protein kinase B/Akt pathway in breast cancer cells.Hlobilkova A et al. · 2006No paper-specific finding is recorded.
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.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 0.010
Open source ↗
ClinVar
3 Likely pathogenic · 1 Pathogenic
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/variation/428277/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692883-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933126-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87933126-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.367C…
- OncoKB ↗www.oncokb.org/gene/PTEN/H123D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139198547
- 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 has been reported in ClinVar as Likely pathogenic (3 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen (expert panel). (ClinVarID = 428277)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.98. BayesDel score = 0.601229.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64294365, n = 3 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.