Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
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.
About PTEN
PTEN is a tumor suppressor gene that encodes a phosphatase converting the lipid messenger PIP3 back to PIP2 at the cell membrane, thereby restraining the AKT/mTOR signaling pathway that drives cell growth, proliferation, and survival. It is one of the most frequently mutated genes across many types of human cancer, and its loss promotes unchecked cell growth, survival, and genomic instability, partly through impaired DNA repair. Germline loss-of-function variants in PTEN cause Cowden syndrome, an inherited cancer predisposition disorder associated with elevated risk of breast and thyroid cancer.
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. 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.
Met (Very Strong): 7-bp frameshift deletion (p.Lys66ThrfsTer31) truncates the protein 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay.
PM2Supporting
PM2 · supporting
Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.001% population-frequency threshold.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ClinGen PTEN Expert Panel ACMG/AMP Specifications v3.2: one Very Strong (PVS1) plus one Supporting (PM2) criterion satisfies Rule 20, yielding 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.
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 2 not met · 11 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PTEN VCEP PVS1 decision tree applied: c.197_203del is a frameshift null variant with premature stop at ~codon 96, 5' of the p.D375 (c.1121) NMD threshold, in biologically-relevant transcript NM_000314.8 -> PVS1 Very Strong.
PM4 not applicable: variant is a frameshift (not in-frame indel, not stop-loss/extension), which falls outside the PTEN VCEP PM4 definition.
BP3 not applicable per explicit PTEN VCEP cspec designation.
NM_000314.8:c.197_203del is a 7-nucleotide in-frame-shifted coding deletion producing NP_000305.3:p.(Lys66ThrfsTer31), a frameshift/premature-truncation consequence rather than a missense substitution.
PS1, PM5, and PP2 are missense-specific criteria under the PTEN VCEP cSpec v3.2 and generic ACMG/AMP framework; none apply to a frameshift variant.
PM1 under PTEN VCEP is defined around catalytic-motif hotspot residues (90-94, 123-130, 166-168) for missense changes; codon 66 falls outside these ranges and the variant is not missense, so PM1 does not apply.
BP1 is marked gene-wide 'Not Applicable' for PTEN by the VCEP cSpec regardless of variant type.
This variant's loss-of-function mechanism (premature truncation) is properly addressed by PVS1-family criteria, outside this group's scope.
PTEN VCEP v3.2 PS3/BS3 rules are variant-type-specific: the Mighell et al. 2018 (PMID:29706350) phosphatase saturation mutagenesis assay applies to missense variants only, and the RNA/mini-gene splicing assay pathway applies to intronic/synonymous variants only.
This variant, NM_000314.8:c.197_203del, is a frameshift (p.(Lys66ThrfsTer31)), so neither VCEP-specified PS3/BS3 assay pathway is applicable and no variant-specific functional data were found in the case bundle.
NM_000314.8:c.197_203del is a 7-bp coding deletion causing a frameshift (NP_000305.3:p.(Lys66ThrfsTer31)), i.e. a predicted null/loss-of-function variant governed by the PTEN VCEP's PVS1 decision tree.
The PTEN VCEP (cspec v3.2) defines PP3 and BP4 rules narrowly for two mechanistic sub-paths only: splicing variants (SpliceAI+VarSeak concordance) and missense variants (REVEL threshold). BP7 is defined only for synonymous/deep-intronic variants. None of these three criteria's variant-class scopes cover a coding frameshift deletion, so all three are assessed as not_applicable rather than met/not_met.
SpliceAI was computed as part of standard prefetch (max delta = 0.038, non-significant) but is not being used to assign PP3/BP4 because this variant is not a splice-region/intronic variant to which the VCEP's splicing sub-path applies.
REVEL and BayesDel scores were not available/not applicable since this is not a missense variant; even if BayesDel had a score, this pipeline has no verified published calibration threshold for it.
Population evidence supports PM2 at the PTEN-specific supporting strength because the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
BA1 and BS1 are not met because no population frequency reaches their PTEN-specific thresholds.
BS2 is not assessed because no homozygous observation with the required health or clinical-status information is documented.
No criteria match.
Met · 2
PVS1Very strongMet (Very Strong): 7-bp frameshift deletion (p.Lys66ThrfsTer31) truncates the protein 5' of the p.D375 threshold, predicted to trigger nonsense-mediated decay.
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Reasoning
NM_000314.8:c.197_203del is a 7-bp deletion (not a multiple of 3) causing a frameshift, NP_000305.3:p.(Lys66ThrfsTer31). Per the PTEN VCEP PVS1 decision tree, the resulting premature stop codon falls at approximately residue 96, which is 5' of the p.D375 (c.1121) positional threshold used by the VCEP to distinguish NMD-predicted from non-NMD variants. The frameshift disrupts the reading frame well upstream of the terminal exon and is predicted to trigger nonsense-mediated decay; the tree assigns PVS1 (Very Strong) to null variants with a stop codon/disruption at or 5' of p.D375 in the biologically-relevant transcript NM_000314.8, which this deletion satisfies as a canonical frameshift/null variant early in the coding sequence.
Rule
PTEN VCEP PVS1 decision tree: stop codon/frameshift disruption at or 5' to p.D375 (c.1121) in biologically-relevant transcript NM_000314.8 -> PVS1 (Very Strong)
Evidence considered
PTEN VCEP PVS1 decision tree (PVS1_DecisionTree_PTEN.pdf) applies NMD prediction and the p.D375 (c.1121) positional threshold to null variants in NM_000314.8: stop codon/disruption at or 5' to p.D375 in the biologically-relevant transcript is assigned PVS1 (Very Strong).
Case normalization data: NM_000314.8:c.197_203del produces NP_000305.3:p.(K66Tfs*31), a frameshift with premature termination at approximately codon 96, well 5' of the p.D375 (c.1121) threshold and not in the terminal exon, consistent with NMD prediction.
PM2SupportingMet (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, below the 0.001% population-frequency threshold.
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Reasoning
The PTEN VCEP permits PM2 at supporting strength when the variant is absent or has gnomAD or another large sequenced population allele frequency below 0.00001 (0.001%); if multiple alleles occur within a subpopulation, the subpopulation frequency must be below 0.00002 (0.002%). The variant is reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, satisfying the specified population-absence threshold.
Rule
Supporting: absent in population; databases present at <0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; if multiple alleles are present within any subpopulation, subpopulation allele frequency must be <0.00002 (0.002%).
Evidence considered
The PTEN VCEP specifies PM2 supporting for databases present at less than 0.00001 (0.001%) allele frequency in gnomAD or another large sequenced population; when multiple alleles are present within any subpopulation, the subpopulation allele frequency must be less than 0.00002 (0.002%).
The case bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, which is below both specified frequency thresholds and supports PM2 at supporting strength.
BA1Not met: variant is absent from gnomAD, so the >0.056% BA1 frequency threshold is not reached.
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Reasoning
The variant is absent from the available gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population datasets; therefore the PTEN-specific BA1 threshold of gnomAD filtering allele frequency >0.00056 (0.056%) is not reached.
Rule
gnomAD Filtering allele frequency >0.00056 (0.056%)
Evidence considered
The PTEN VCEP specifies BA1 as a gnomAD filtering allele frequency greater than 0.00056 (0.056%).
The case bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so no frequency supports BA1.
BS1Not met: variant is absent from gnomAD, so neither the strong nor supporting BS1 frequency interval is reached.
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Reasoning
The variant is absent from the available gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population datasets; therefore neither the PTEN-specific BS1 strong interval (0.000043 to 0.00056) nor the supporting interval (0.0000043 to 0.000043) is reached.
Rule
Strong: gnomAD Filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%); Supporting: allele frequency from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
Evidence considered
The PTEN VCEP specifies BS1 strong for gnomAD filtering allele frequency from 0.000043 (0.0043%) up to 0.00056 (0.056%), and BS1 supporting from 0.0000043 (0.00043%) up to 0.000043 (0.0043%).
The case bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so no frequency supports BS1 at either strength.
PS2Not assessed: no proband, de novo observation, or parental-testing results were available.
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Reasoning
No case-level evidence is provided for a patient with disease, absence of family history, confirmed maternity and paternity, or a proven de novo observation. The available bundle contains no proband or parental-testing result that permits assessment of PS2.
Rule
De novo (both maternity and paternity confirmed) observation in a patient with the disease and no family history.
Evidence considered
The PTEN Expert Panel specification lists PS2 as applicable and requires a de novo observation with both maternity and paternity confirmed in a patient with the disease and no family history for strong evidence.
The consolidated case-evidence bundle contains no proband, pedigree, parental-testing, or de novo observation data for NM_000314.8:c.197_203del.
Still missing
Proband-level phenotype and disease diagnosis
Documented absence of family history
Parental testing confirming both maternity and paternity
Variant presence in the proband and absence in both biological parents
PS3Not assessed: the VCEP functional assay covers only missense variants, and no variant-specific functional study was available.
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Reasoning
NM_000314.8:c.197_203del (NP_000305.3:p.(Lys66ThrfsTer31)) is a frameshift variant. The ClinGen PTEN VCEP specification (v3.2) restricts its named PS3 functional-assay pathway (Mighell et al. 2018, PMID:29706350 Table S2 phosphatase saturation mutagenesis, Cum_score <= -1.11 for PS3_Moderate) to missense substitutions, and the VCEP local index file (mmc2.xlsx) explicitly scopes this assay to variant type 'missense' only, so this frameshift cannot be looked up in that dataset. The VCEP splicing-assay pathway for PS3_Strong applies only to variants with a demonstrated splicing mechanism, and SpliceAI predicts no significant splice impact for this variant (max delta 0.038), so a splicing assay is not the relevant mechanism. No variant-specific in vitro or in vivo functional study of this frameshift/truncating allele was identified in the case evidence bundle. The two functional-theme PMIDs retrieved (PMID:11237521, PMID:17218262) are general PTEN tumor-suppressor/phosphatase biology reviews and do not mention this specific variant, so per strict citation-grounding rules they cannot be used to support PS3.
Still missing
No variant-specific functional/enzymatic assay (e.g., phosphatase activity, protein stability/expression, localization) identified for NM_000314.8:c.197_203del or its resulting truncated protein product.
Mighell et al. 2018 (PMID:29706350) massively parallel phosphatase assay dataset (mmc2.xlsx) covers only missense substitutions and does not include this frameshift allele.
PS4Not assessed: no case-control counts, odds ratios, or phenotype-specificity data were available for this variant.
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Reasoning
The PTEN Expert Panel permits PS4 using either a qualifying case-control enrichment result or phenotype-specificity scoring across unrelated probands. This bundle contains no case-control counts, odds ratio, p value, confidence interval, proband-level Cleveland Clinic scores, pediatric phenotype scores, or qualifying unrelated case series for NM_000314.8:c.197_203del. The variant is absent from ClinVar and no phenotype prevalence evidence is provided.
Rule
PTEN Expert Panel Version 3.2: case-control enrichment or cumulative phenotype-specificity score; PS4 Very Strong >=16, PS4 4-15.5, PS4 Moderate 2-3.5, PS4 Supporting 1-1.5. Do not combine PS4 with PP4.
Evidence considered
PTEN Expert Panel Version 3.2 defines PS4 Very Strong at a cumulative phenotype-specificity score of at least 16, PS4 at 4-15.5, PS4 Moderate at 2-3.5, and PS4 Supporting at 1-1.5; it also permits a qualifying case-control enrichment result.
The case bundle provides no case-control analysis, phenotype-specificity scores, or qualifying unrelated proband data for this exact variant.
The exact variant search in ClinVar returned no result, so it does not provide expert-panel or case-series evidence for PS4.
Still missing
Need a sufficiently powered case-control study with variant or phenotype counts and statistical results, or qualifying unrelated proband-level PTEN phenotype-specificity scores.
PS4 cannot be applied together with PP4 under the PTEN Expert Panel specification.
PM6Not assessed: no documented de novo occurrence or parental-testing results were available.
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Reasoning
No assumed de novo occurrence is documented in a proband with PTEN hamartoma tumor syndrome or another qualifying disease phenotype and no family history. Maternity and paternity confirmation status and parental variant testing are absent.
Rule
Assumed de novo, but without confirmation of paternity and maternity, in proband with the disease and no family history.
Evidence considered
The PTEN Expert Panel specification defines PM6 as assumed de novo evidence without confirmation of paternity and maternity, with higher strengths requiring multiple qualifying occurrences or a highly specific phenotype.
The consolidated case-evidence bundle contains no qualifying de novo case observations for NM_000314.8:c.197_203del.
Still missing
One or more documented probands with disease
Evidence of no family history for each proband
Parental testing or other basis for presumed de novo status
PP1Not assessed: no affected relatives or segregation results were reported.
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Reasoning
No affected relatives, segregation results, pedigree, or countable meioses are reported for this variant. Therefore co-segregation cannot be assessed and no PP1 strength can be assigned.
Rule
Co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed.
Evidence considered
The PTEN Expert Panel specification requires 3 or 4 meioses for PP1 supporting, 5 or 6 meioses for PP1 moderate, and at least 7 meioses across at least two families for PP1 strong.
The consolidated case-evidence bundle contains no family segregation data or informative meiosis count for NM_000314.8:c.197_203del.
Still missing
Pedigree and affected-relative phenotypes
Variant testing results in affected relatives
Number of informative meioses
Evidence that the phenotype is consistent with PTEN-related disease in segregating relatives
PP5Not assessed: no exact-variant ClinVar expert-panel classification was available.
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Reasoning
PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification under the requested adjudication rule. The case bundle reports no exact ClinVar result, no variation ID, no classification, and no review status. OncoKB and literature records are not ClinVar expert-panel assertions and cannot trigger PP5.
Rule
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; otherwise do not apply.
Evidence considered
The exact variant ClinVar search returned no result; variation_ids, classification, and review_status are empty.
No ordinary laboratory submission, aggregate ClinVar label, non-expert assertion, OncoKB label, or literature classification was counted for PP5.
Still missing
Need an exact-match ClinVar expert-panel Pathogenic or Likely pathogenic classification with identifiable review status.
BS2Not assessed: no homozygous observations in healthy or unaffected individuals were available.
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Reasoning
No evidence in the case bundle documents the variant in the homozygous state in a healthy or PHTS-unaffected individual, and the population records are reported only as absent rather than providing homozygote observations.
Rule
Strong: observed in the homozygous state in a healthy or PHTS-unaffected individual; one observation if homozygous status confirmed, two if not confirmed. Supporting: two homozygous observations with no clinical data, or meets BS2 but BS1 is also applied.
Evidence considered
The PTEN VCEP specifies BS2 strong for one confirmed homozygous observation in a healthy or PHTS-unaffected individual, or two observations if homozygous status is not confirmed; BS2 is supporting when BS1 is also applied or for two homozygous observations without clinical data.
The case bundle reports the variant as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 but provides no homozygote observation or clinical status.
Still missing
A confirmed homozygous observation in a healthy or PHTS-unaffected individual is not available.
Two homozygous observations without clinical data are not documented.
BS3Not assessed: the VCEP benign functional assay covers only missense variants, and no variant-specific study was available.
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Reasoning
The ClinGen PTEN VCEP specification (v3.2) BS3_Supporting pathway using Mighell et al. 2018 (PMID:29706350, Table S2, Cum_score > 0) is explicitly scoped by the VCEP local index (mmc2.xlsx) to missense variants only, so it cannot be applied to this frameshift variant, NM_000314.8:c.197_203del (NP_000305.3:p.(Lys66ThrfsTer31)). The VCEP BS3_Strong splicing pathway applies only to intronic/synonymous variants assessed by RNA/mini-gene assay, which does not apply here (this is a coding frameshift, not a splice-region variant). No variant-specific functional study showing lack of a damaging effect was identified for this variant.
Still missing
No variant-specific functional assay data available showing normal/wild-type-like activity for this frameshift allele.
Mighell et al. 2018 (PMID:29706350) dataset scope is limited to missense variants and does not apply to this frameshift.
BS4Not assessed: no family members lacking the variant were documented, so lack of segregation could not be established.
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Reasoning
No affected family members who lack the variant are documented. Consequently, lack of segregation cannot be established in one family or in two or more families.
Rule
Lack of segregation in affected members of one family.
Evidence considered
The PTEN Expert Panel specification permits BS4 supporting for lack of segregation in one family and BS4 strong for lack of segregation in two or more families, while cautioning that phenocopies and more than one pathogenic variant can confound interpretation.
The consolidated case-evidence bundle contains no affected-relative testing or non-segregation data for NM_000314.8:c.197_203del.
Still missing
Affected relatives evaluated for the variant
Reliable phenotype assessment and age-related penetrance information for relatives
Pedigree-level evidence of non-segregation in at least one family
A second independent family if strong BS4 is considered
BP2Not assessed: no cis, trans, or phase observations with pathogenic PTEN variants were available.
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Reasoning
The PTEN Expert Panel permits BP2 at Supporting strength when the variant is observed in trans with a pathogenic or likely pathogenic PTEN variant, or when there are at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants. The case-evidence bundle contains no affected-proband, family, parental-testing, phase, cis, or trans observations for NM_000314.8:c.197_203del, so BP2 cannot be assessed.
Rule
Observed in trans with a pathogenic or likely pathogenic PTEN variant OR at least three observations in cis and/or phase unknown with different pathogenic/likely pathogenic PTEN variants.
Evidence considered
The PTEN Expert Panel BP2 rule requires observation in trans with a pathogenic or likely pathogenic PTEN variant, or at least three observations in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants.
The consolidated case-evidence bundle reports no case-level or literature phase observations for this variant; the literature pass contains no segregation or case-observation records.
The available ClinVar record search found no result for this variant, and the available evidence does not establish any allelic relationship with another PTEN variant.
Still missing
Documented observation of NM_000314.8:c.197_203del in trans with a pathogenic or likely pathogenic PTEN variant, including phase evidence and the affected-proband context.
Alternatively, at least three independent observations of the variant in cis and/or phase unknown with different pathogenic or likely pathogenic PTEN variants.
Parental or offspring testing and the phase relationship for any allelic observations are not available in the case-evidence bundle.
BP5Not assessed: no cases with an alternate molecular basis or non-overlapping phenotype were available.
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Reasoning
The PTEN Expert Panel requires at least two cases with an alternate molecular basis, a highly penetrant alternate gene or disorder, and personal or family history showing no overlap with PTEN. The case bundle contains no such cases or clinical histories for this exact variant.
Rule
PTEN Expert Panel Version 3.2: BP5 Supporting requires at least two cases with a highly penetrant alternate gene/disorder and no phenotype overlap with PTEN.
Evidence considered
PTEN Expert Panel Version 3.2 requires at least two cases and the specified highly penetrant alternate-diagnosis and non-overlapping-history conditions for BP5.
The supplied case-evidence bundle contains no alternate molecular diagnosis or qualifying personal/family history for this variant.
Still missing
Need at least two exact-variant cases with a documented alternate molecular diagnosis, evidence that the alternate condition is highly penetrant, and non-overlapping personal/family histories relative to PTEN hamartoma tumor syndrome.
Not applicable · 13· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: a frameshift deletion produces no discrete amino-acid change to compare against a pathogenic missense precedent.
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Reasoning
PS1 requires a variant that produces the same amino acid change as a previously established pathogenic variant (or a same-nucleotide-position splicing comparator). NM_000314.8:c.197_203del produces NP_000305.3:p.(Lys66ThrfsTer31), a frameshift/premature-stop consequence, not a discrete missense amino-acid substitution. There is no single 'amino acid change' for PS1 to compare against a missense pathogenic precedent, so PS1 is not applicable to this variant class.
Evidence considered
PTEN VCEP cSpec v3.2 defines PS1 (Strong) as requiring the same amino acid change as an established pathogenic variant, or a same-nucleotide-position splicing comparator with in silico support equal/greater impact.
Variant is a 7-bp coding deletion causing frameshift p.(Lys66ThrfsTer31) per case_summary.json normalization, not a missense substitution; PS1's missense-comparator mechanism does not apply.
PM1N/ANot applicable: a frameshift at codon 66 lies outside the catalytic-motif hotspot residues 90-94, 123-130, and 166-168.
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Reasoning
PTEN VCEP PM1 (Moderate) is defined for variants located in the catalytic-motif hotspot residues 90-94, 123-130, or 166-168 (NP_000305.3), a rule built around missense substitutions affecting a specific catalytic residue's function. This variant affects codon 66 (outside all three defined catalytic-motif ranges) and is a frameshift deletion, not a missense change altering a single residue's side chain within the motif. The deleterious mechanism here is loss-of-function via premature truncation, which is captured under PVS1, not the missense positional/domain mechanism PM1 addresses.
Evidence considered
PTEN VCEP cSpec v3.2 PM1 rule text: 'Located in a mutational hot spot and/or critical and well-established functional domain. Defined to include residues in catalytic motifs: 90-94, 123-130, 166-168 (NP_000305.3).'
Variant residue is Lys66, outside the defined catalytic motif ranges 90-94/123-130/166-168; variant type is frameshift, not missense.
gnomAD hotspot lookup (cancerhotspots.org query 'PTEN K66') returned no significant hotspot result.
PM3VCEPNot applicable: designated not applicable by the PTEN Expert Panel because PTEN hamartoma tumor syndrome is autosomal dominant.
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Reasoning
The ClinGen PTEN Expert Panel specification, Version 3.2, designates PM3 as not applicable. PTEN hamartoma tumor syndrome is autosomal dominant, so the recessive-disorder compound-heterozygous/in-trans PM3 criterion is not used.
VCEP rule
This rule is not applicable to PTEN.
Evidence considered
The PTEN Expert Panel specification states: PM3 applicability is Not applicable and the rule is not applicable to PTEN.
The framework identifies the PTEN disorder inheritance mode as autosomal dominant inheritance.
No publication was specifically reviewed because PM3 is not applicable under the governing PTEN framework.
PM4N/ANot applicable: the 7-bp deletion causes a frameshift, not an in-frame length change or stop-loss protein extension.
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Reasoning
The PTEN VCEP specification restricts PM4 to protein length changes from in-frame insertions/deletions in a non-repeat region, or stop-loss variants (extending the protein). c.197_203del is a 7-bp deletion causing a frameshift (not in-frame) with a premature termination codon, not a protein extension. It does not fit either PM4 scenario defined by the VCEP, so PM4 is not applicable to this variant class; the variant's loss-of-function consequence is already captured under PVS1.
Rule
PTEN VCEP: PM4 applies to in-frame indels (non-repeat region) or stop-loss extensions only; excludes frameshift/null variants
Evidence considered
PTEN VCEP cspec (v3.2) PM4 rule: applies only to protein length changes from in-frame indels in non-repeat regions (or catalytic-motif-impacting in-frame indels) or stop-loss/extension variants; this frameshift deletion is neither in-frame nor a stop-loss/extension event.
PM5N/ANot applicable: this is a frameshift deletion, not a missense change, so no BLOSUM62 comparison applies.
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Reasoning
PM5 (Moderate) requires a missense change at a residue where a different missense change has already been established pathogenic/likely pathogenic, with BLOSUM62 scoring of the interrogated variant versus the known variant. This variant is a frameshift deletion (p.Lys66ThrfsTer31), not a missense amino-acid substitution, so there is no BLOSUM62-comparable missense change to evaluate and PM5's mechanism does not apply.
Evidence considered
PTEN VCEP cSpec v3.2 PM5 rule requires a missense change with BLOSUM62 comparison to a known pathogenic missense change at the same residue; this variant produces a frameshift, not a missense substitution, so the criterion's applicability condition is not met.
PP2N/ANot applicable: PP2 applies only to missense variants; this is a frameshift deletion.
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Reasoning
PP2 (Supporting) applies specifically to missense variants in a gene with a low rate of benign missense variation where missense is a common disease mechanism. This variant is a frameshift/indel, not a missense variant, so PP2 does not apply regardless of PTEN's missense constraint profile.
Evidence considered
PTEN VCEP cSpec v3.2 PP2 rule text explicitly scoped to 'Missense variant in a gene that has a low rate of benign missense variation...'; this variant is a coding deletion causing frameshift, not a missense substitution.
PP3N/ANot applicable: the VCEP computational pathway covers only missense (REVEL) and splicing variants, not frameshift deletions.
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Reasoning
NM_000314.8:c.197_203del is a 7-bp coding deletion causing a frameshift (NP_000305.3:p.(Lys66ThrfsTer31)). The PTEN VCEP (cspec v3.2) PP3 rule is scoped explicitly to two variant classes: (1) splicing variants, evaluated by concordance of SpliceAI and VarSeak, and (2) missense variants, evaluated by REVEL score > 0.7. This variant is neither a splice-region/intronic variant nor a missense substitution -- it is a frameshifting indel whose primary predicted mechanism (loss of function via premature termination/NMD) is governed by the VCEP's PVS1 decision tree, not by calibrated computational splice/missense predictors. No REVEL score applies (not a missense change) and there is no VCEP-defined computational pathway for frameshift deletions under PP3. SpliceAI was run as part of standard prefetch (max delta = 0.038, non-significant) but this variant is not positioned at a splice consensus sequence, so the splice sub-path is not the applicable mechanism here either. Because neither VCEP-defined computational sub-path (splicing or missense) applies to a coding frameshift deletion, PP3 is not applicable.
Rule
PTEN VCEP PP3 (cspec v3.2): applies only to splicing variants (SpliceAI+VarSeak concordance) or missense variants (REVEL>0.7); not applicable to frameshift deletions.
Evidence considered
PTEN VCEP (cspec v3.2) PP3 rule text: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL score > 0.7.' -- variant type coverage is restricted to splicing and missense classes.
Case normalization: NM_000314.8:c.197_203del is a 7-nucleotide in-frame-incompatible (7 is not a multiple of 3) coding deletion producing p.(Lys66ThrfsTer31), i.e. a frameshift, not a missense or splice-region variant.
SpliceAI prefetch result: max delta score = 0.038 (DS_AG 0.0, DS_AL 0.035, DS_DG 0.0, DS_DL 0.038), well below any significance threshold, consistent with this deletion not disrupting a splice consensus sequence, though this is not the operative reason for non-applicability since the variant class itself is outside the VCEP PP3 scope.
PP4VCEPNot applicable: designated not applicable by the PTEN Expert Panel; phenotype specificity is covered under PS4.
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Reasoning
PP4 is explicitly designated not applicable in the PTEN Expert Panel Version 3.2 specification because phenotype specificity is incorporated into PS4 Use 2.
VCEP rule
PTEN Expert Panel Version 3.2: PP4 not applicable; use the phenotype-specificity provisions under PS4 instead.
Evidence considered
The PTEN Expert Panel specification states that phenotype specificity has been incorporated into the PS4 rule specifications and marks PP4 as not applicable.
BP1VCEPNot applicable: designated not applicable gene-wide by the PTEN VCEP; also a frameshift, not a missense change.
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Reasoning
The PTEN VCEP cSpec v3.2 explicitly marks BP1 as 'Not Applicable' gene-wide for PTEN (no missense-tolerant subregion exemption is defined). Independently, BP1 (benign missense mechanism) could not apply here regardless, since this variant is a frameshift, not a missense change.
Evidence considered
PTEN VCEP cSpec v3.2 lists BP1 applicability as 'Not Applicable' for the PTEN gene overall.
Variant is a frameshift deletion, not a missense substitution, providing an independent basis for non-applicability.
BP3VCEPNot applicable: designated not applicable for PTEN by the VCEP specification.
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Reasoning
The PTEN VCEP specification (v3.2) explicitly marks BP3 as Not Applicable for this gene, so it is not assessed regardless of variant type. This is also consistent generically since BP3 (in-frame indel in a repetitive region with no known function) does not apply to a frameshift/null variant such as this 7-bp deletion.
VCEP rule
PTEN VCEP: BP3 not applicable for PTEN per cspec v3.2
Evidence considered
PTEN VCEP cspec (v3.2) marks BP3 applicability as 'Not Applicable' for the PTEN gene-specific specification.
BP4N/ANot applicable: BP4 applies only to missense (REVEL) and splicing variants; this is a frameshift deletion.
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Reasoning
Mirroring PP3, the PTEN VCEP BP4 rule is scoped to splicing variants (SpliceAI/VarSeak concordance of no impact) and missense variants (REVEL < 0.5). NM_000314.8:c.197_203del is a frameshift-causing coding deletion (p.(Lys66ThrfsTer31)), not a missense substitution, and is not a splice-site/intronic variant subject to the splicing sub-path. There is no REVEL score (variant is not missense) and no VCEP-defined benign computational pathway for frameshift indels; BayesDel has no verified published calibration threshold available to this pipeline and could not be used in any case. SpliceAI shows a non-significant max delta (0.038), but this variant's class places it outside the VCEP's BP4 applicability, not within a 'concordant benign splice' finding. BP4 is therefore not applicable to this variant type.
Rule
PTEN VCEP BP4 (cspec v3.2): applies only to splicing variants (SpliceAI+VarSeak concordance of no impact) or missense variants (REVEL<0.5); not applicable to frameshift deletions.
Evidence considered
PTEN VCEP (cspec v3.2) BP4 rule text: 'Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL scores < 0.5.' -- scope limited to splicing and missense classes.
Variant is a 7-bp coding deletion causing frameshift p.(Lys66ThrfsTer31), not missense and not a splice-region/intronic variant, so neither VCEP BP4 sub-path is applicable.
BayesDel score not available/not verified for this pipeline (no named publication with a calibrated threshold), so it could not be used for BP4 regardless of variant class.
SpliceAI prefetch: max delta score = 0.038, non-significant, but not determinative here because the variant class (frameshift deletion) is outside VCEP BP4 scope.
BP6VCEPNot applicable: designated not applicable by the PTEN Expert Panel, and the variant is absent from ClinVar.
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Reasoning
BP6 is marked not applicable for the PTEN Expert Panel, which states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact variant is also absent from ClinVar, so there is no expert-panel Benign or Likely benign classification.
VCEP rule
BP6 is not applicable under PTEN Expert Panel Version 3.2; under the requested rule it could only be considered for an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
The PTEN Expert Panel specification marks BP6 not applicable and states that it is not for use.
The exact variant ClinVar search returned no result; no expert-panel Benign or Likely benign classification is available.
Ordinary laboratory submissions, aggregate ClinVar labels, non-expert assertions, and other database labels were not used to trigger BP6.
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants; this is a coding frameshift deletion.
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Reasoning
PTEN VCEP BP7 (cspec v3.2) applies only to synonymous (silent) variants or intronic variants at or beyond +7/-21 where splicing prediction algorithms predict no impact. NM_000314.8:c.197_203del is a coding frameshift deletion (p.(Lys66ThrfsTer31)), not a synonymous substitution and not an intronic variant, so BP7 cannot apply regardless of the (non-significant) SpliceAI result.
Rule
PTEN VCEP BP7 (cspec v3.2): applies only to synonymous or intronic (+7/-21 or beyond) variants; not applicable to frameshift deletions.
Evidence considered
PTEN VCEP (cspec v3.2) BP7 rule text: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.' Variant is a coding frameshift deletion, not synonymous or intronic, so BP7 is out of scope.
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—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele 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
SpliceAI acceptor lossat -30 bp
0.035
SpliceAI acceptor gainat -77 bp
0.000
SpliceAI donor lossat +18 bp
0.038
SpliceAI donor gainat +97 bp
0.000
Pangolin splice lossmagnitude shown
-0.054
Pangolin splice gain
0.008
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: the VCEP computational pathway covers only missense (REVEL) and splicing variants, not frameshift deletions.
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Reasoning
NM_000314.8:c.197_203del is a 7-bp coding deletion causing a frameshift (NP_000305.3:p.(Lys66ThrfsTer31)). The PTEN VCEP (cspec v3.2) PP3 rule is scoped explicitly to two variant classes: (1) splicing variants, evaluated by concordance of SpliceAI and VarSeak, and (2) missense variants, evaluated by REVEL score > 0.7. This variant is neither a splice-region/intronic variant nor a missense substitution -- it is a frameshifting indel whose primary predicted mechanism (loss of function via premature termination/NMD) is governed by the VCEP's PVS1 decision tree, not by calibrated computational splice/missense predictors. No REVEL score applies (not a missense change) and there is no VCEP-defined computational pathway for frameshift deletions under PP3. SpliceAI was run as part of standard prefetch (max delta = 0.038, non-significant) but this variant is not positioned at a splice consensus sequence, so the splice sub-path is not the applicable mechanism here either. Because neither VCEP-defined computational sub-path (splicing or missense) applies to a coding frameshift deletion, PP3 is not applicable.
Rule
PTEN VCEP PP3 (cspec v3.2): applies only to splicing variants (SpliceAI+VarSeak concordance) or missense variants (REVEL>0.7); not applicable to frameshift deletions.
Evidence considered
PTEN VCEP (cspec v3.2) PP3 rule text: 'Multiple lines of computational evidence support a deleterious effect on the gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL score > 0.7.' -- variant type coverage is restricted to splicing and missense classes.
Case normalization: NM_000314.8:c.197_203del is a 7-nucleotide in-frame-incompatible (7 is not a multiple of 3) coding deletion producing p.(Lys66ThrfsTer31), i.e. a frameshift, not a missense or splice-region variant.
SpliceAI prefetch result: max delta score = 0.038 (DS_AG 0.0, DS_AL 0.035, DS_DG 0.0, DS_DL 0.038), well below any significance threshold, consistent with this deletion not disrupting a splice consensus sequence, though this is not the operative reason for non-applicability since the variant class itself is outside the VCEP PP3 scope.
BP4N/ANot applicable: BP4 applies only to missense (REVEL) and splicing variants; this is a frameshift deletion.
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Reasoning
Mirroring PP3, the PTEN VCEP BP4 rule is scoped to splicing variants (SpliceAI/VarSeak concordance of no impact) and missense variants (REVEL < 0.5). NM_000314.8:c.197_203del is a frameshift-causing coding deletion (p.(Lys66ThrfsTer31)), not a missense substitution, and is not a splice-site/intronic variant subject to the splicing sub-path. There is no REVEL score (variant is not missense) and no VCEP-defined benign computational pathway for frameshift indels; BayesDel has no verified published calibration threshold available to this pipeline and could not be used in any case. SpliceAI shows a non-significant max delta (0.038), but this variant's class places it outside the VCEP's BP4 applicability, not within a 'concordant benign splice' finding. BP4 is therefore not applicable to this variant type.
Rule
PTEN VCEP BP4 (cspec v3.2): applies only to splicing variants (SpliceAI+VarSeak concordance of no impact) or missense variants (REVEL<0.5); not applicable to frameshift deletions.
Evidence considered
PTEN VCEP (cspec v3.2) BP4 rule text: 'Multiple lines of computational evidence suggest no impact on gene or gene product. Splicing variants: Concordance of SpliceAI and VarSeak; Missense variants: REVEL scores < 0.5.' -- scope limited to splicing and missense classes.
Variant is a 7-bp coding deletion causing frameshift p.(Lys66ThrfsTer31), not missense and not a splice-region/intronic variant, so neither VCEP BP4 sub-path is applicable.
BayesDel score not available/not verified for this pipeline (no named publication with a calibrated threshold), so it could not be used for BP4 regardless of variant class.
SpliceAI prefetch: max delta score = 0.038, non-significant, but not determinative here because the variant class (frameshift deletion) is outside VCEP BP4 scope.
BP7N/ANot applicable: BP7 applies only to synonymous or intronic variants; this is a coding frameshift deletion.
Details ▾Hide ▴
Reasoning
PTEN VCEP BP7 (cspec v3.2) applies only to synonymous (silent) variants or intronic variants at or beyond +7/-21 where splicing prediction algorithms predict no impact. NM_000314.8:c.197_203del is a coding frameshift deletion (p.(Lys66ThrfsTer31)), not a synonymous substitution and not an intronic variant, so BP7 cannot apply regardless of the (non-significant) SpliceAI result.
Rule
PTEN VCEP BP7 (cspec v3.2): applies only to synonymous or intronic (+7/-21 or beyond) variants; not applicable to frameshift deletions.
Evidence considered
PTEN VCEP (cspec v3.2) BP7 rule text: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice.' Variant is a coding frameshift deletion, not synonymous or intronic, so BP7 is out of scope.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
2 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.
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
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