About PTEN
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTEN c.238A>G, p.(Lys80Glu)
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
PS3_Moderate is met per PTEN VCEP specification. The variant p.Lys80Glu (K80E) was directly assayed in the Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional study of PTEN phosphatase activity. The cumulative fitness score (Cum_score) from Table S2 of the study is -1.60681967, which is ≤ -1.11, meeting the VCEP threshold for PS3_Moderate. The measurement is flagged as high confidence (High_conf=True).
PM2Supporting
PM2 · supporting
PM2_Supporting is met per PTEN VCEP specification. The variant is absent from gnomAD v2.1 and v4.1 (allele frequency < 0.00001 / 0.001%), meeting the VCEP threshold for population absence. Absent also in gnomAD-Canada v1.0.
PP2Supporting
PP2 · supporting
PP2 is met per PTEN VCEP specification. PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PTEN. The variant p.Lys80Glu is a missense substitution.
PP3Supporting
PP3 · supporting
PP3 is met per PTEN VCEP specification for missense variants. The REVEL score for this variant is 0.775, which exceeds the VCEP threshold of >0.7 for multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for this missense variant and does not contradict the REVEL-based PP3 call.
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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV64290643, n = 1 times).
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.
26 criteria with recorded statuses: 4 met · 14 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PTEN c.238A>G (p.Lys80Glu) is a missense variant in exon 4 of the phosphatase domain.
The variant is absent from population databases (gnomAD v2.1 and v4.1), meeting PM2_Supporting per PTEN VCEP.
Functional data from Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis assay demonstrates a cumulative fitness score of -1.60681967, below the -1.11 threshold for PS3_Moderate, indicating significantly reduced phosphatase activity with high confidence.
Computational evidence supports pathogenicity: REVEL score 0.775 (>0.7 threshold for PP3) per PTEN VCEP specification.
PP2 is applied as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism.
No benign criteria are met: variant is absent from population databases (BA1/BS1 not met), no homozygous observations (BS2 not met), functional data shows damaging effect (BS3 not met), REVEL exceeds benign threshold (BP4 not met).
Under the PTEN VCEP v3.2.0 combination rules, this evidence set (PS3_Moderate + PM2_Supporting + PP2 + PP3 = 1 moderate + 3 supporting) does not trigger any Pathogenic or Likely Pathogenic classification rule. The variant is classified as Variant of Uncertain Significance (VUS).
No criteria match.
Met · 4
PS3 ModeratePS3_Moderate is met per PTEN VCEP specification. The variant p.Lys80Glu (K80E) was directly assayed in the Mighell et al. 2018 (PMID: 29706350) saturation mutagenesis functional study of PTEN phosphatase activity. The cumulative fitness score (Cum_score) from Table S2 of the study is -1.60681967, which is ≤ -1.11, meeting the VCEP threshold for PS3_Moderate. The measurement is flagged as high confidence (High_conf=True). Details ▾Hide ▴
Evidence considered
- Mighell et al. 2018 Table S2: K80E Cum_score = -1.60681967 (≤ -1.11 threshold)
- High_conf=True
Sources
PM2 SupportingPM2_Supporting is met per PTEN VCEP specification. The variant is absent from gnomAD v2.1 and v4.1 (allele frequency < 0.00001 / 0.001%), meeting the VCEP threshold for population absence. Absent also in gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF < 0.001%)
- Absent from gnomAD v4.1 (AF < 0.001%)
Sources
PP2 SupportingPP2 is met per PTEN VCEP specification. PTEN has a low rate of benign missense variation and missense variants are a common mechanism of disease in PTEN. The variant p.Lys80Glu is a missense substitution. Details ▾Hide ▴
Evidence considered
- PTEN has low rate of benign missense variation
- missense is a common disease mechanism
Sources
PP3 SupportingPP3 is met per PTEN VCEP specification for missense variants. The REVEL score for this variant is 0.775, which exceeds the VCEP threshold of >0.7 for multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for this missense variant and does not contradict the REVEL-based PP3 call. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.775 (>0.7 threshold)
- BayesDel score = 0.174
- SpliceAI max delta = 0.01 (no splice impact)
Sources
Not met · 14 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change as a previously established pathogenic variant regardless of nucleotide change, or a different variant at the same nucleotide position as a known pathogenic splicing variant. No other nucleotide change resulting in p.Lys80Glu has been identified as a previously established pathogenic variant, nor is there a known pathogenic splicing variant at c.238. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at residue 80 established as pathogenic
Sources
PS2 PS2 requires a de novo observation with both maternity and paternity confirmed in a patient with the disease and no family history. No published de novo case of PTEN c.238A>G with confirmed parentage was identified in indexed literature or clinical databases. Details ▾Hide ▴
Evidence considered
- PubMed search for PTEN Lys80Glu de novo returned no confirmed de novo cases
Still missing
- Internal laboratory data or DECIPHER may contain de novo observations
PM1 The PTEN VCEP defines PM1 as located in a mutational hot spot and/or critical functional domain, specifically residues in catalytic motifs: 90-94, 123-130, and 166-168 (NP_000305.3). The variant p.Lys80Glu is at position 80, which lies outside all three defined catalytic motif ranges. Although residue 80 is within the broader phosphatase domain (residues 7-185), the VCEP specification restricts PM1 to the enumerated catalytic motifs. Details ▾Hide ▴
Evidence considered
- Residue 80 not in VCEP-defined catalytic motifs (90-94
- 123-130
- 166-168)
Sources
PM5 PM5 requires a missense change at an amino acid residue where a different missense change has been determined to be pathogenic or likely pathogenic, with the interrogated variant having a BLOSUM62 score equal to or less than the known variant. No different missense change at PTEN residue 80 (Lys) has been established as pathogenic or likely pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- 0 same-residue pathogenic/likely pathogenic comparator variants at K80
Sources
pm5_candidates
PM6 PM6 requires an assumed de novo occurrence (without confirmation of paternity and maternity) in a proband with the disease and no family history. No de novo reports, confirmed or unconfirmed, were identified for PTEN c.238A>G in the literature or clinical databases. Details ▾Hide ▴
Evidence considered
- No de novo observations found in PubMed or ClinVar submissions
Still missing
- Unconfirmed de novo observations may exist in clinical databases not publicly indexed
PP1 PP1 requires co-segregation with disease in multiple affected family members with ≥3 meioses (PTEN VCEP: 3-4 meioses = Supporting, 5-6 = Moderate, ≥7 across ≥2 families = Strong). No co-segregation data or family studies involving PTEN c.238A>G were identified. Details ▾Hide ▴
Evidence considered
- No co-segregation data available
Still missing
- Family studies or internal laboratory segregation data needed
BA1 BA1 requires a gnomAD filtering allele frequency >0.00056 (0.056%) per PTEN VCEP. The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0.0, which does not meet the BA1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (AF = 0.0
- threshold >0.056%)
Sources
BS1 BS1 requires a gnomAD filtering allele frequency of ≥0.0000043 (0.00043%) for Supporting or ≥0.000043 (0.0043%) for Strong per PTEN VCEP. The variant is absent from gnomAD v2.1 and v4.1 (AF = 0.0), which does not meet either BS1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 and v4.1 (AF = 0.0
- below BS1 thresholds)
Sources
BS2 BS2 requires observation in the homozygous state in a healthy or PHTS-unaffected individual (Strong for one confirmed homozygous, Supporting for two unconfirmed or if BS1 also applied). No homozygous observations of PTEN c.238A>G were identified in gnomAD or any other source. Details ▾Hide ▴
BS3 BS3_Supporting per PTEN VCEP requires phosphatase activity >0 in the Mighell et al. 2018 assay (PMID: 29706350). The variant K80E has a cumulative fitness score (Cum_score) of -1.60681967, which is well below 0, indicating damaging effect on phosphatase activity. BS3 is not met. BS3_Strong for splicing assays showing no impact is not applicable as this is not a splicing variant. Details ▾Hide ▴
Evidence considered
- K80E Cum_score = -1.60681967 (<0 threshold for BS3_Supporting)
Sources
BS4 BS4 requires lack of segregation in affected members of one family (Supporting) or two or more families (Strong) per PTEN VCEP. No segregation data, positive or negative, were identified for PTEN c.238A>G. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Family-based segregation studies needed
BP2 BP2 requires observation in trans with a pathogenic or likely pathogenic PTEN variant or at least three observations in cis/phase unknown with different P/LP PTEN variants per the VCEP specification. No such observations were identified for PTEN c.238A>G. Details ▾Hide ▴
Evidence considered
- No trans or cis observations with other P/LP PTEN variants
BP4 BP4 for missense variants per PTEN VCEP requires REVEL score <0.5. The REVEL score for PTEN c.238A>G is 0.775, which exceeds the benign threshold and is instead consistent with a deleterious prediction (supporting PP3). BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.775 (>0.5 benign threshold)
Sources
revel
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease, where the other gene/disorder is highly penetrant and the patient's personal/family history shows no overlap with PTEN. No such case has been reported for PTEN c.238A>G. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular basis identified
Not assessed · 1 · no assessment recorded
PS4 PS4 requires proband counts with specificity scores per PTEN VCEP thresholds. The ClinVar record (variation ID 571869) shows a single clinical laboratory submission classified as Pathogenic (review status: criteria provided, single submitter). The submission audit found 0 usable submissions and 0 criterion-lead submissions. Exact proband counts with phenotype specificity scores are not available from the current evidence. PS4 cannot be applied without quantified proband data. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submitter
- Pathogenic
- single submitter
- 0 usable submissions
Still missing
- Proband counts with PS4 specificity scores needed from clinical laboratories or published cohorts
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. The PTEN VCEP PVS1 decision tree applies only to nonsense, frameshift, canonical ±1,2 splice site disruptions, and CNVs. NM_000314.8:c.238A>G (p.Lys80Glu) is a missense substitution in exon 4 and does not fall into any null-variant bucket. Details ▾Hide ▴
Evidence considered
- PVS1 decision tree limited to null variants
- missense variant K80E does not qualify
Sources
vcep_pvs1_decisiontree_ptenpvs1_variant_assessment
PP4 VCEPPP4 is designated as Not Applicable by the PTEN VCEP. Phenotype specificity has been incorporated into the rule specifications for PS4 Use 2. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is designated as Not Applicable by the PTEN VCEP. This criterion is not used in the PTEN expert panel specification. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is designated as Not Applicable by the PTEN VCEP. This criterion (missense variant in a gene where primarily truncating variants cause disease) does not apply to PTEN under the expert panel specification. Details ▾Hide ▴
Sources
BP6 VCEPBP6 is designated as Not Applicable by the PTEN VCEP. This criterion (reputable source classifies as benign) is not used in the PTEN expert panel specification. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. NM_000314.8:c.238A>G is a missense variant (p.Lys80Glu), not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
PS5 N/APS5 applies when a reputable source recently reports a variant as pathogenic but the evidence is not available for independent evaluation. This variant is being directly evaluated through the PTEN VCEP framework; its classification is being determined here rather than adopted from an external source. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- PTEN
- Transcript
- NM_000314.8
- Coding (HGVS c.)
- NM_000314.8:c.238A>G
- Protein (HGVS p.)
- NP_000305.3:p.(Lys80Glu)
- GRCh38
- chr10:87931074 A>G
- GRCh37
- chr10:89690831 A>G
- ClinVar
- 571869
- COSMIC
- COSV64290643
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in PTEN
—
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.775
- BayesDel
- 0.174
How the predictions were used
PP3 SupportingPP3 is met per PTEN VCEP specification for missense variants. The REVEL score for this variant is 0.775, which exceeds the VCEP threshold of >0.7 for multiple lines of computational evidence supporting a deleterious effect. SpliceAI predicts no significant splice impact (max delta = 0.01), which is expected for this missense variant and does not contradict the REVEL-based PP3 call. Details ▾Hide ▴
Evidence considered
- REVEL score = 0.775 (>0.7 threshold)
- BayesDel score = 0.174
- SpliceAI max delta = 0.01 (no splice impact)
Sources
BP4 BP4 for missense variants per PTEN VCEP requires REVEL score <0.5. The REVEL score for PTEN c.238A>G is 0.775, which exceeds the benign threshold and is instead consistent with a deleterious prediction (supporting PP3). BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.775 (>0.5 benign threshold)
Sources
revel
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond +7/-21 for which splicing prediction algorithms predict no splice impact. NM_000314.8:c.238A>G is a missense variant (p.Lys80Glu), not a synonymous or intronic variant. BP7 is not applicable. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.775. BayesDel score = 0.173785.
9 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
-
PMID 20712882 ↗Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations.Banneau G et al. · 2010No paper-specific finding is recorded.
-
PMID 23335809 ↗High cumulative risks of cancer in patients with PTEN hamartoma tumour syndrome.Bubien V et al. · 2013No paper-specific finding is recorded.
-
PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.Syngal S et al. · 2015No paper-specific finding is recorded.
-
PMID 28263967 ↗Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization.Yang JM et al. · 2017No paper-specific finding is recorded.
-
PMID 29706350 ↗A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships.Mighell TL et al. · 2018No paper-specific finding is recorded.
-
PMID 17392385 ↗American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.Saslow D et al. · 2007No paper-specific finding is recorded.
-
PMID 20301661 ↗PTEN Hamartoma Tumor Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
-
PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013No paper-specific finding is recorded.
-
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
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/?term=NM_000314.8%3Ac.238A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-89690831-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-87931074-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000314.8%3Ac.238A…
- OncoKB ↗www.oncokb.org/gene/PTEN/K80E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=139187763
- 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
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.775. BayesDel score = 0.173785.
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; COSV64290643, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.