About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.722T>C, p.(Phe241Ser)
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
This missense variant showed reduced PTEN function in the Mighell et al. phosphatase assay, with Cum_score -2.399 and High_conf=True; this is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11 and supports a damaging effect on PTEN function.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%).
PP2Supporting
PP2 · supporting
This is a missense variant in PTEN, a gene for which missense variants are a common disease mechanism and benign missense variation is relatively constrained, so PP2 is met.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel PP3 threshold of >0.7.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
PTEN CSPEC/VCEP cspec_ruleset v3.2.0 final-classification framework (Richards et al. 2015 combining rules) from final_classification_framework.json; applied criteria were PS3_Moderate, PM2_Supporting, PP2, and PP3.
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 classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
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 · 7 not met · 8 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.722T>C (p.Phe241Ser) variant has been observed in somatic cancers in COSMIC (COSV64294827, 5 occurrences) and has not been reported in the current ClinVar record set.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed allele frequency of 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%).
Functional studies support a damaging effect on PTEN, including a Mighell et al. phosphatase assay result of Cum_score -2.399 with High_conf=True, which is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11; OncoKB also describes the variant as Likely Oncogenic with a likely loss-of-function effect.
Computational evidence supports a deleterious effect for the missense change because the REVEL score is 0.858, above the PTEN Expert Panel PP3 threshold of >0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.
No criteria match.
Met · 4
PS3 ModerateThis missense variant showed reduced PTEN function in the Mighell et al. phosphatase assay, with Cum_score -2.399 and High_conf=True; this is below the PTEN Expert Panel PS3_Moderate threshold of <= -1.11 and supports a damaging effect on PTEN function. Details ▾Hide ▴
Rule
Phosphatase activity <= -1.11 per Mighell et al. 2018.
Evidence considered
- mmc2 Table S2: F241S Cum_score=-2.399434227
- mmc2 Table S2: High_conf=True
- OncoKB: Likely Oncogenic; biological effect Likely Loss-of-function
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed allele frequency is 0, which is below the PTEN Expert Panel PM2_Supporting threshold of <0.00001 (0.001%). Details ▾Hide ▴
Rule
Absent or ultra-rare in population databases at <0.00001 allele frequency.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
PP2 SupportingThis is a missense variant in PTEN, a gene for which missense variants are a common disease mechanism and benign missense variation is relatively constrained, so PP2 is met. 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 p.(Phe241Ser)
- PTEN CSPEC retains PP2 as applicable for missense variants
Sources
PP3 SupportingComputational evidence supports a deleterious effect for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel PP3 threshold of >0.7. Details ▾Hide ▴
Rule
Missense variants: REVEL score >0.7.
Evidence considered
- REVEL=0.858
Sources
revel
Not met · 7 · evaluated, threshold not reached
PS1 No different nucleotide change producing the same PTEN p.(Phe241Ser) amino acid substitution was identified as a previously established pathogenic variant, so PS1 is not met. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- Current ClinVar search found no record for NM_000314.8:c.722T>C
- mmc2 Table S3 lists the same nucleotide change c.722T>C rather than an alternate nucleotide change with the same amino acid outcome
Sources
PM1 PTEN p.(Phe241Ser) affects residue 241, which is outside the PTEN catalytic motifs defined for PM1 (residues 90-94, 123-130, and 166-168), so PM1 is not met. Details ▾Hide ▴
Rule
Located in a mutational hot spot and/or critical well-established functional domain defined for PTEN catalytic motifs.
Evidence considered
- Protein change p.(Phe241Ser)
- PTEN PM1 motifs are residues 90-94, 123-130, and 166-168
Sources
PM5 No different pathogenic or likely pathogenic missense change at PTEN residue Phe241 was identified, so PM5 is not met. Details ▾Hide ▴
Rule
Different pathogenic or likely pathogenic missense change at the same residue with equal or lower BLOSUM62 score.
Evidence considered
- Current ClinVar search found no record for this variant
- mmc2 Table S3 shows p.Phe241Leu as uncertain significance, not pathogenic/likely pathogenic
Sources
BA1 This variant is absent from gnomAD, so the observed allele frequency is 0, which is below the PTEN Expert Panel BA1 threshold of >0.00056 (0.056%). Details ▾Hide ▴
Rule
gnomAD filtering allele frequency >0.00056.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
BS1 This variant is absent from gnomAD, so the observed allele frequency is 0, which is below the PTEN Expert Panel BS1 thresholds of >=0.0000043 and therefore does not support a benign frequency-based interpretation. Details ▾Hide ▴
Rule
Allele frequency between 0.0000043 and 0.00056, depending on strength.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
BS3 Available functional evidence does not show normal PTEN function. In the Mighell et al. assay, this variant had Cum_score -2.399, which is not above the PTEN Expert Panel BS3_Supporting threshold of >0 and therefore does not support BS3. Details ▾Hide ▴
Rule
Phosphatase activity >0 per Mighell et al. 2018 for BS3_Supporting.
Evidence considered
- mmc2 Table S2: F241S Cum_score=-2.399434227
- OncoKB: Likely Loss-of-function
Sources
BP4 Computational evidence does not support a benign interpretation for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel BP4 threshold of <0.5, even though SpliceAI predicts no meaningful splice effect with a max delta score of 0.01. Details ▾Hide ▴
Rule
Missense variants: REVEL score <0.5.
Evidence considered
- REVEL=0.858
- SpliceAI max delta=0.01
Sources
revelspliceai ↗
Not assessed · 8 · no assessment recorded
PS2 No proven de novo observation with confirmed maternity and paternity in an affected individual and no family history was identified, so PS2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.
Evidence considered
- mmc2 Table S5 includes a curated de novo F241S report but does not document parental confirmation
Still missing
- Parental confirmation data
- Family history status
- Primary case-level publication details
Sources
vcep_m_m_c_2PMID:29706350 ↗
PS4 Available evidence does not provide a PTEN phenotype specificity score, a qualifying case-control comparison, or sufficiently detailed germline proband data to apply PS4. Details ▾Hide ▴
Rule
Probands with specificity score or significant increased prevalence in affected individuals versus controls.
Evidence considered
- ClinVar has no current submission for this variant
- mmc2 Table S5 lists curated observations but not enough PTEN EP scoring detail
Still missing
- PTEN phenotype specificity scoring
- Eligible germline proband count
- Case-control enrichment data
Sources
PM6 One curated de novo observation was identified, but the available summary does not document absence of family history or enough independent de novo observations to meet the PTEN Expert Panel PM6 thresholds. Details ▾Hide ▴
Rule
Assumed de novo occurrence in a patient with disease and no family history, with strength based on number of observations.
Evidence considered
- mmc2 Table S5: F241S listed once as de novo in ASD/DD
Still missing
- Primary publication review for de novo evidence
- Family history details
- Number of independent probands
Sources
vcep_m_m_c_2PMID:29706350 ↗
PP1 No segregation data with informative meioses were identified, so PP1 cannot be applied. Details ▾Hide ▴
Rule
Co-segregation with disease in multiple affected family members.
Still missing
- Family segregation data
BS2 No homozygous observation in a healthy or PTEN hamartoma tumor syndrome-unaffected individual was identified, so BS2 cannot be applied. Details ▾Hide ▴
Rule
Observed in the homozygous state in a healthy or PHTS-unaffected individual.
Still missing
- Unaffected homozygous observation data
BS4 No lack-of-segregation data in affected family members were identified, so BS4 cannot be applied. Details ▾Hide ▴
Rule
Lack of segregation in affected members of one or more families.
Still missing
- Family segregation data
BP2 No phase data showing this variant in trans with a pathogenic PTEN variant or repeated in cis/phase-unknown observations with pathogenic PTEN variants were identified, so BP2 cannot be applied. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic/likely pathogenic PTEN variant or repeated cis/unknown-phase observations.
Still missing
- Phase data with pathogenic PTEN variants
BP5 No evidence was identified that this variant was found in at least two cases with a separate highly penetrant molecular diagnosis and non-overlapping PTEN-related phenotype, so BP5 cannot be applied. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease under PTEN EP restrictions.
Still missing
- Alternate molecular diagnosis case data
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, canonical +/-1,2 splice, initiation codon, or exon-level loss-of-function variant, so the PTEN-specific PVS1 decision tree does not apply. Details ▾Hide ▴
Rule
Use PTEN PVS1 decision tree.
Evidence considered
- NM_000314.8:c.722T>C encodes p.(Phe241Ser)
- pvs1_variant_assessment variant_bucket=other
- PTEN PVS1 decision tree is for null-variant classes
Sources
PM3 N/APM3 is not applicable for the PTEN Expert Panel framework. Details ▾Hide ▴
PM4 N/AThis variant is a missense substitution and does not cause an in-frame insertion, in-frame deletion, stop-loss, or protein extension, so PM4 does not apply. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- Protein change is p.(Phe241Ser) missense
Sources
PP4 N/APP4 is not applicable in the PTEN Expert Panel framework because phenotype specificity is incorporated into PS4 scoring. Details ▾Hide ▴
PP5 N/APP5 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
BP1 N/ABP1 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
BP3 N/ABP3 is not applicable for PTEN in the Expert Panel framework. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in the PTEN Expert Panel framework. Details ▾Hide ▴
BP7 N/AThis is not a synonymous or qualifying intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Protein change is missense p.(Phe241Ser)
Sources
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.722T>C
- Protein (HGVS p.)
- NP_000305.3:p.(Phe241Ser)
- GRCh38
- chr10:87957940 T>C
- GRCh37
- chr10:89717697 T>C
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 0.858, which is above the PTEN Expert Panel PP3 threshold of >0.7. Details ▾Hide ▴
Rule
Missense variants: REVEL score >0.7.
Evidence considered
- REVEL=0.858
Sources
revel
BP4 Computational evidence does not support a benign interpretation for this missense variant because the REVEL score is 0.858, which is above the PTEN Expert Panel BP4 threshold of <0.5, even though SpliceAI predicts no meaningful splice effect with a max delta score of 0.01. Details ▾Hide ▴
Rule
Missense variants: REVEL score <0.5.
Evidence considered
- REVEL=0.858
- SpliceAI max delta=0.01
Sources
revelspliceai ↗
BP7 N/AThis is not a synonymous or qualifying intronic variant, so BP7 does not apply. Details ▾Hide ▴
Rule
Synonymous or intronic variant at or beyond +7/-21 with no predicted splice impact.
Evidence considered
- Protein change is missense p.(Phe241Ser)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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.722T%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89717697-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87957940-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.722T…
- OncoKB ↗www.oncokb.org/gene/PTEN/F241S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=117176404
- 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).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV64294827, n = 5 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.