About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.368A>G, p.(His123Arg)
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
PTEN H123R (His123Arg) has a cumulative fitness score (Cum_score) of -3.83 in the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis phosphatase activity assay. This score is ≤ -1.11, meeting the PTEN VCEP threshold for PS3_Moderate. The measurement is high-confidence (High_conf = True, Pass SE Filter).
PM1Moderate
PM1 · moderate
Residue His123 is located within the PTEN phosphatase catalytic motif defined by the VCEP as residues 123-130 (NP_000305.3). This meets the PTEN VCEP PM1_Moderate criterion for missense variants located in a critical functional domain.
PM2Supporting
PM2 · supporting
c.368A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per PTEN VCEP rules, absence from large sequenced population databases (< 0.001% allele frequency) meets PM2_Supporting.
PM6Moderate
PM6 · moderate
The ClinGen PTEN Variant Curation Expert Panel (SCV000863477) explicitly applied PM6 at the Moderate level, noting 'assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history.' This expert panel determination is followed directly. The de novo observation is referenced to Nelen et al. 1999 (PMID:10234502).
PP2Supporting
PP2 · supporting
PTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Per PTEN VCEP rules, PP2_Supporting applies to missense variants.
PP3Supporting
PP3 · supporting
REVEL score is 0.985, which exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.01), consistent with a missense mechanism rather than splicing defect. BayesDel score of 0.61462 also supports a deleterious prediction.
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, PM6 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
4 Pathogenic.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64309701, n = 4 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.
29 criteria with recorded statuses: 7 met · 5 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
c.368A>G (p.His123Arg) is a missense variant in exon 5 of PTEN, within the phosphatase catalytic motif (residues 123-130).
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under PTEN VCEP rules.
His123 is located within the VCEP-defined catalytic motif, meeting PM1_Moderate.
The variant has been classified as Pathogenic by the ClinGen PTEN Variant Curation Expert Panel (ClinVar SCV000863477, reviewed by expert panel).
In the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis phosphatase activity assay, H123R has a cumulative fitness score of -3.83 (High_conf = True), meeting the PTEN VCEP threshold for PS3_Moderate (Cum_score <= -1.11).
The ClinGen PTEN VCEP applied PM6_Moderate, noting an assumed de novo occurrence (parentage unconfirmed) in a patient with Cowden syndrome (Nelen et al. 1999, PMID:10234502).
Computational evidence supports pathogenicity: REVEL score 0.985 meets PP3_Supporting; PTEN's low rate of benign missense variation supports PP2_Supporting.
The ClinGen PTEN VCEP classification as Pathogenic supports PP5_Supporting, applied per user directive to override VCEP Not Applicable when expert panel classification exists.
No criteria match.
Met · 7
PS3 ModeratePTEN H123R (His123Arg) has a cumulative fitness score (Cum_score) of -3.83 in the Mighell et al. 2018 (PMID:29706350) saturation mutagenesis phosphatase activity assay. This score is ≤ -1.11, meeting the PTEN VCEP threshold for PS3_Moderate. The measurement is high-confidence (High_conf = True, Pass SE Filter). Details ▾Hide ▴
Evidence considered
- Mighell et al. 2018 massively parallel phosphatase activity assay: H123R Cum_score = -3.834
- High_conf = True.
Sources
cspec ↗vcep_mmc2
PM1 ModerateResidue His123 is located within the PTEN phosphatase catalytic motif defined by the VCEP as residues 123-130 (NP_000305.3). This meets the PTEN VCEP PM1_Moderate criterion for missense variants located in a critical functional domain. Details ▾Hide ▴
Evidence considered
- His123 is within the VCEP-defined catalytic motif residues 123-130 of the phosphatase domain.
Sources
PM2 Supportingc.368A>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per PTEN VCEP rules, absence from large sequenced population databases (< 0.001% allele frequency) meets PM2_Supporting. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles)
- gnomAD v4.1 (0 alleles)
- and gnomAD-Canada v1.0 (0 alleles).
Sources
PM6 ModerateThe ClinGen PTEN Variant Curation Expert Panel (SCV000863477) explicitly applied PM6 at the Moderate level, noting 'assumed de novo, but without confirmation of paternity and maternity in a patient with the disease and no family history.' This expert panel determination is followed directly. The de novo observation is referenced to Nelen et al. 1999 (PMID:10234502). Details ▾Hide ▴
PP2 SupportingPTEN is a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. Per PTEN VCEP rules, PP2_Supporting applies to missense variants. Details ▾Hide ▴
Evidence considered
- PTEN has low benign missense variation rate
- missense variants are a common disease mechanism.
Sources
PP3 SupportingREVEL score is 0.985, which exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.01), consistent with a missense mechanism rather than splicing defect. BayesDel score of 0.61462 also supports a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.985 (> 0.7 threshold)
- BayesDel = 0.615
- SpliceAI max delta = 0.01 (no splicing impact).
Sources
PP5 SupportingExpert panel Clingen PTEN Variant Curation Expert Panel, Clingen classified as Pathogenic. Details ▾Hide ▴
Not met · 5 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. No evidence was found of p.His123Arg caused by a different nucleotide substitution with a prior pathogenic classification. Details ▾Hide ▴
Still missing
- No alternate nucleotide change producing H123R identified as pathogenic.
BA1 c.368A>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The PTEN VCEP BA1 threshold requires filtering allele frequency > 0.056%. The variant does not meet this threshold. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD populations
- allele frequency = 0
- which does not exceed the BA1 threshold (0.056%).
Sources
BS1 c.368A>G is absent from gnomAD. The PTEN VCEP BS1 threshold requires filtering allele frequency from 0.000043 (0.0043%) to 0.00056 (0.056%). The variant's allele frequency of 0 does not fall within the BS1 benign range. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD populations
- allele frequency = 0
- below the BS1 benign range (0.000043-0.00056).
Sources
BS3 PTEN H123R has a Cum_score of -3.83 in the Mighell et al. 2018 functional assay (PMID:29706350). BS3 requires phosphatase activity > 0 (BS3_Supporting) or a well-established functional study showing no damaging effect (BS3). The Cum_score is strongly negative, indicating damaging effect, which contradicts the benign evidence required for BS3. Details ▾Hide ▴
Evidence considered
- Mighell et al. 2018: H123R Cum_score = -3.834
- indicating damaging effect
- does not meet BS3 thresholds (> 0 or no damaging effect).
Sources
vcep_mmc2cspec ↗
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. For missense variants per PTEN VCEP, REVEL score < 0.5 is required. REVEL for c.368A>G is 0.985, strongly predicting a damaging effect. BayesDel (0.615) also supports a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.985 (> 0.5 threshold for BP4)
- BayesDel = 0.615 (deleterious). Both contradict BP4.
Sources
Not assessed · 9 · no assessment recorded
PS2 ClinVar submissions (SCV004103762, SCV000617322) and the ClinGen PTEN VCEP (SCV000863477) reference a de novo occurrence in Nelen et al. 1999 (PMID:10234502). The VCEP applied PM6 (assumed de novo, unconfirmed parentage) rather than PS2 (confirmed de novo). Full text of PMID:10234502 was not available for independent confirmation. Without direct verification of the de novo report, PS2 cannot be assessed independently. Details ▾Hide ▴
Evidence considered
- ClinGen PTEN VCEP submission notes assumed de novo in a patient with Cowden syndrome
- parentage not confirmed.
Still missing
- Full text of PMID:10234502 (Nelen et al. 1999) not available for independent de novo confirmation.
Sources
PS4 PS4 requires variant-specific proband counts with phenotype specificity scores. No proband counts or phenotype specificity data were available for this variant in the evidence packet. Details ▾Hide ▴
Still missing
- Proband counts and phenotype specificity scores not available.
PM5 PM5 requires a different pathogenic or likely pathogenic missense variant at the same amino acid residue (His123). The pipeline did not identify any comparator missense variants at His123 with P/LP classification. Without a validated comparator, PM5 cannot be applied. Details ▾Hide ▴
Still missing
- No pathogenic/likely pathogenic comparator missense variant at His123 identified.
PP1 No co-segregation data were available for this variant. PP1 requires observation of co-segregation with disease in multiple affected family members across a specified number of meioses. Details ▾Hide ▴
Still missing
- Co-segregation data not available.
BS2 BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual. No homozygous observations were reported in gnomAD or other sources. Details ▾Hide ▴
Still missing
- No homozygous observations reported.
BS4 BS4 requires lack of segregation in affected family members (two or more families for Strong, one family for Supporting). No segregation data were available for this variant. Details ▾Hide ▴
Still missing
- Segregation data not available.
BP2 BP2 requires observation in trans with a pathogenic/likely pathogenic PTEN variant or at least three observations in cis/phase unknown. No such observations were available. Details ▾Hide ▴
Still missing
- No in trans or cis observations reported.
BP5 BP5 requires a variant found in a case with an alternate molecular basis for disease where the other gene/disorder is highly penetrant and the patient's history does not overlap with PTEN. No such case was identified. Details ▾Hide ▴
Still missing
- No case with alternate molecular basis identified.
PS5 No independent evidence was identified to support PS5. This criterion is typically used for variants where additional independent data confirm pathogenicity beyond what other criteria capture. Details ▾Hide ▴
Still missing
- No independent PS5-level evidence identified.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/Ac.368A>G is a missense variant (p.His123Arg). The PTEN PVS1 decision tree (VCEP v3.2.0) applies only to null variants (nonsense, frameshift, canonical GT-AG splice site disruptions, and exon-level CNVs). Missense variants do not qualify for PVS1 adjudication under this framework. Details ▾Hide ▴
Evidence considered
- VCEP PVS1 decision tree restricted to null variant classes
- c.368A>G is missense.
Sources
PM3 VCEPThe PTEN VCEP designates PM3 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/Ac.368A>G is a missense substitution, not an in-frame deletion/insertion or stop-loss variant. PM4 applies to protein length changes from in-frame indels or stop-loss variants. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPThe PTEN VCEP designates PP4 as Not Applicable. Phenotype specificity is incorporated into PS4 rule specifications instead. Details ▾Hide ▴
BP1 VCEPThe PTEN VCEP designates BP1 as Not Applicable. Details ▾Hide ▴
BP3 VCEPc.368A>G is a single-nucleotide substitution, not an in-frame deletion or insertion. BP3 applies only to in-frame indels in non-repeat regions. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPThe PTEN VCEP designates BP6 as Not Applicable. Details ▾Hide ▴
BP7 N/Ac.368A>G is a missense variant, not a synonymous (silent) or intronic variant. BP7 applies only to synonymous and deep intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous/intronic variants only.
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.368A>G
- Protein (HGVS p.)
- NP_000305.3:p.(His123Arg)
- GRCh38
- chr10:87933127 A>G
- GRCh37
- chr10:89692884 A>G
- ClinVar
- 301419, 7816
- COSMIC
- COSV64309701
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
- 0.985
- BayesDel
- 0.615
How the predictions were used
PP3 SupportingREVEL score is 0.985, which exceeds the PTEN VCEP PP3 threshold of > 0.7 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.01), consistent with a missense mechanism rather than splicing defect. BayesDel score of 0.61462 also supports a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.985 (> 0.7 threshold)
- BayesDel = 0.615
- SpliceAI max delta = 0.01 (no splicing impact).
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on the gene product. For missense variants per PTEN VCEP, REVEL score < 0.5 is required. REVEL for c.368A>G is 0.985, strongly predicting a damaging effect. BayesDel (0.615) also supports a deleterious prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.985 (> 0.5 threshold for BP4)
- BayesDel = 0.615 (deleterious). Both contradict BP4.
Sources
BP7 N/Ac.368A>G is a missense variant, not a synonymous (silent) or intronic variant. BP7 applies only to synonymous and deep intronic variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous/intronic variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.985. BayesDel score = 0.61462.
8 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 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 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 23161105 ↗A new insight into structural and functional impact of single-nucleotide polymorphisms in PTEN gene.George Priya Doss C et al. · 2013No paper-specific finding is recorded.
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PMID 25527629 ↗Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.Spinelli L et al. · 2015Spinelli et al. studied functional consequences of seven autism-associated PTEN missense mutations (H118P, H123Q, E157G, F241S, D252G, N276S, D326N) and five severe PHTS-associated mutations (A39P, N48K, L108P, L112P, R130L). NM_000314.8:c.368A>G (p.His123Arg) was not among the variants studied. H123Q was studied and found to retain AKT-suppressive activity with normal protein stability.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards et al. 2015 ACMG/AMP standards and guidelines for sequence variant interpretation. This is a general framework document that does not discuss specific PTEN variants.Does not name this variant
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PMID 26800850 ↗Prediction of functionally significant single nucleotide polymorphisms in PTEN tumor suppressor gene: An in silico approach.Khan I et al. · 2017No 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
4 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/7816/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89692884-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87933127-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-87933127-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.368A…
- OncoKB ↗www.oncokb.org/gene/PTEN/H123R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139188479
- 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 Pathogenic (4 clinical laboratories) and as Pathogenic by Clingen PTEN Variant Curation Expert Panel, Clingen (expert panel). (ClinVarID = 7816)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.985. BayesDel score = 0.61462.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64309701, n = 4 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.