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This variantScenario
BenignPathogenic
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
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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.
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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.
ACMG/AMP criteria under ClinGen PTEN VCEP v3.2, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 4 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PTEN CSPEC v3.2 governs this gene; PVS1 is adjudicated via the PTEN-specific PVS1 decision tree rather than generic ACMG PVS1 guidance.
The variant (NM_000314.8:c.775_781del, p.His259ArgfsTer5) is a frameshift deletion truncating the protein well before the VCEP's c.1121/p.D375 NMD cutoff, so PVS1 (Very Strong) is met.
PM4 and BP3 both concern in-frame protein length changes and are not applicable to this frameshift-class variant; BP3 is additionally excluded outright by the PTEN CSPEC as Not Applicable.
NM_000314.8:c.775_781del produces NP_000305.3:p.(His259ArgfsTer5), a frameshift consequence, not a missense substitution or in-frame indel touching a defined catalytic motif.
All five codon/residue/domain criteria in this group (PS1, PM1, PM5, PP2, BP1) are defined by the PTEN VCEP specification (and generic ACMG/AMP) for missense variants (or, for PM1/PM4, in-frame indels within catalytic motifs); none of those conditions are met by this frameshift deletion, so all are not_applicable.
This variant's evidentiary weight is expected to derive from PVS1/frameshift-null pathways handled by other criterion groups, not from residue/domain-specific missense criteria.
PTEN VCEP (cspec v3.2) PS3/BS3 evidentiary pathways are variant-type restricted: the quantitative Mighell et al. 2018 (PMID:29706350) phosphatase-activity dataset (mmc2.xlsx) covers missense substitutions only, and the RNA/splicing-assay pathway applies to intronic/synonymous/splice-impacting variants. NM_000314.8:c.775_781del is a frameshift deletion (p.His259ArgfsTer5), so neither pathway is applicable, and no variant-specific functional study was found in the literature packet. Both PS3 and BS3 are therefore not_assessed rather than not_applicable, since a frameshift could in principle be functionally characterized (e.g., protein stability/NMD escape studies) even though no such study exists in the current evidence bundle.
NM_000314.8:c.775_781del is a 7-bp coding deletion resulting in a frameshift, p.(His259ArgfsTer5) — not a missense, synonymous, or splice-region/intronic variant.
The PTEN VCEP (cspec v3.2) scopes its PP3/BP4 computational-evidence rules exclusively to 'Splicing variants' (SpliceAI+VarSeak concordance) and 'Missense variants' (REVEL threshold); BP7 is scoped to synonymous/deep-intronic variants only. This frameshift deletion matches none of these categories, so PP3, BP4, and BP7 are all not_applicable under the governing VCEP framework.
SpliceAI was queried for completeness and shows no significant splice-altering signal (max delta = 0.037), consistent with the variant's mechanism being frameshift/nonsense-mediated decay (addressed separately under PVS1) rather than a splicing disruption; this finding does not itself trigger PP3, BP4, or BP7 given the categorical scope mismatch, and no VarSeak result was available in the evidence bundle to establish the concordance the VCEP rule requires in any case.
REVEL and BayesDel are not applicable/not available for this indel (evidence bundle: revel skipped as 'not snv or no coords'; bayesdel score/found = null), consistent with this not being a missense variant.
No criteria match.
Met · 2
PVS1Very strongMet (Very Strong): frameshift p.(His259ArgfsTer5) truncates well before the PTEN VCEP NMD cutoff at c.1121, predicting nonsense-mediated decay.
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Reasoning
NM_000314.8:c.775_781del (NP_000305.3:p.(His259ArgfsTer5)) is a 7-bp deletion causing a frameshift with a premature stop codon at residue 264, well upstream of the PTEN VCEP NMD/positional cutoff at c.1121 (p.D375). Per the PTEN VCEP PVS1 decision tree (PVS1_DecisionTree_PTEN.pdf) and the VCEP's written instructions, frameshift variants predicted to trigger nonsense-mediated decay, with disruption at or 5' of c.1121/p.D375 in the biologically-relevant transcript NM_000314.8, are assigned full PVS1 strength. Germline loss of function is an established PTEN disease mechanism per the CSPEC (PVS1 gene gate: eligible), and the truncation occurs in an exon confirmed present in the clinically relevant transcript NM_000314.8, well before the last exon, so NMD is expected rather than escape.
Rule
PTEN VCEP PVS1 decision tree (frameshift, NMD-predicted, disruption 5' of c.1121/p.D375) -> PVS1 (Very Strong)
Evidence considered
PTEN VCEP PVS1 decision tree: frameshift variants with stop codon or disruption at or 5' to p.D375 (c.1121) in biologically-relevant transcript NM_000314.8 are assigned full PVS1.
Variant truncates protein at residue ~264 (p.His259ArgfsTer5), which is at/5' of the c.1121/p.D375 cutoff, so NMD is predicted per the VCEP rule rather than escape.
pvs1_gene_context.json confirms germline LoF is an established PTEN disease mechanism per official CSPEC (pvs1_gene_gate: eligible).
pvs1_variant_assessment.json classifies the variant consequence_class as frameshift and confirms apply_generic_pvs1_framework logic is superseded here by the gene-specific PTEN decision tree, which is more specific and takes precedence.
PM2SupportingMet (Supporting): absent from gnomAD v2.1 and v4.1, below the PTEN 0.001% allele-frequency threshold.
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Reasoning
PM2_Supporting is met under the PTEN Expert Panel specification: the variant is absent from gnomAD v2.1 and gnomAD v4.1, satisfying the requirement for absence or allele frequency <0.00001 (0.001%).
Rule
PTEN Expert Panel v3.2 PM2_Supporting: absent in population databases or allele frequency <0.00001 (0.001%); if multiple alleles are present in a subpopulation, subpopulation allele frequency must be <0.00002 (0.002%).
Evidence considered
gnomAD v2.1 direct-variant query (GRCh37 10-89717748-TCCACAAA-T) returned absent.
gnomAD v4.1 direct-variant query (GRCh38 chr10-87957991-TCCACAAA-T) returned absent.
ClinGen PTEN Expert Panel Specifications v3.2 assign PM2 at Supporting strength for absence or allele frequency <0.00001 (0.001%) in gnomAD or another large sequenced population; if multiple alleles occur in a subpopulation, subpopulation allele frequency must be <0.00002 (0.002%).
BA1Not met: absent from gnomAD v2.1 and v4.1, far below the PTEN BA1 threshold of >0.056% allele frequency.
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Reasoning
BA1 is not met: the variant is absent from gnomAD v2.1 and gnomAD v4.1, so it does not exceed the PTEN Expert Panel filtering allele-frequency threshold of >0.00056 (0.056%).
BS1Not met: absent from gnomAD v2.1 and v4.1, below the PTEN BS1 frequency ranges.
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Reasoning
BS1 is not met: the variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not reach either PTEN Expert Panel BS1 frequency range.
Rule
PTEN Expert Panel v3.2 BS1: Strong at gnomAD filtering allele frequency 0.000043 to 0.00056; Supporting at allele frequency 0.0000043 to 0.000043.
Evidence considered
gnomAD v2.1 direct-variant query (GRCh37 10-89717748-TCCACAAA-T) returned absent.
gnomAD v4.1 direct-variant query (GRCh38 chr10-87957991-TCCACAAA-T) returned absent.
ClinGen PTEN Expert Panel Specifications v3.2 define BS1 Strong as filtering allele frequency 0.000043 to 0.00056 and BS1 Supporting as allele frequency 0.0000043 to 0.000043.
PS2Not assessed: no parental test results or parentage confirmation were available to establish a confirmed de novo occurrence.
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Reasoning
No case-level proband phenotype, parental test results, parentage confirmation, or family-history data are supplied. A confirmed de novo occurrence therefore cannot be established.
Rule
PTEN VCEP PS2: strong requires a de novo observation with both maternity and paternity confirmed in a patient with the disease and no family history; very strong requires two proven, four assumed, or one proven plus two assumed de novo observations.
Evidence considered
The PTEN Expert Panel specifies PS2 at strong strength for a de novo observation in a patient with the disease and no family history when both maternity and paternity are confirmed; its very-strong tier requires multiple de novo observations.
The consolidated evidence bundle contains no proband-level clinical phenotype, parental genotypes, parentage testing, or family-history information for NM_000314.8:c.775_781del.
Still missing
Obtain the proband's PTEN-associated phenotype and family history.
Obtain parental testing showing the variant absent in both biological parents, with maternity and paternity confirmed.
PS3Not assessed: VCEP functional-evidence rules cover only missense (Mighell assay) or splice variants, and no variant-specific functional study of this frameshift was available.
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Reasoning
ClinGen PTEN VCEP specification (cspec v3.2) defines PS3 rules keyed to: (1) RNA/mini-gene splicing assay evidence for splice-impacting variants, or (2) the Mighell et al. 2018 (PMID:29706350) PTEN saturation mutagenesis phosphatase-activity dataset (mmc2.xlsx), which is explicitly scoped by the VCEP index to missense variants only. NM_000314.8:c.775_781del is a frameshift variant (p.His259ArgfsTer5), not a missense substitution, so it has no lookup entry in the Mighell Table S2 Cum_score dataset (which is indexed by single amino-acid substitution codes). SpliceAI predicts no significant splice impact (max delta 0.037), and the variant is coding (not intronic/synonymous), so the RNA/splicing-assay PS3 pathway is also not applicable. No variant-specific in vitro or in vivo functional study of this frameshift allele was found in the literature packet; the only functional-themed PMIDs retrieved (PMID:11237521, PMID:17218262) are general PTEN biology/tumor-suppressor mechanism reviews with no mention of this specific variant.
Still missing
No PS3-qualifying functional assay (phosphatase activity, protein stability, or splicing) has been performed or reported specifically for NM_000314.8:c.775_781del / p.(His259ArgfsTer5).
The PTEN VCEP's only curated quantitative functional dataset (Mighell et al. 2018 mmc2.xlsx) is restricted to missense variants and does not cover frameshift alleles.
PS4Not assessed: no affected-case observations or case-control enrichment data for this exact variant were available.
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Reasoning
No eligible affected-case observations, phenotype-specificity scores, or case-control enrichment data for this exact variant were supplied.
Rule
PTEN EP PS4: case-control enrichment meeting the specified statistical threshold, or aggregate independent-proband phenotype-specificity score (supporting 1-1.5; moderate 2-3.5; strong 4-15.5; very strong >=16).
Evidence considered
The PTEN Expert Panel permits PS4 based on an adequately powered PHTS-component phenotype case-control study (odds ratio >2, p<0.05, and 95% confidence-interval lower bound >1.5), or an aggregate phenotype-specificity score: supporting 1-1.5, moderate 2-3.5, strong 4-15.5, and very strong >=16. The supplied case materials contain no qualifying observations or study.
Still missing
Independent affected probands with phenotypic data sufficient to calculate PTEN EP adult Cleveland Clinic or pediatric specificity scores, or a sufficiently powered case-control study meeting the PTEN EP threshold, are needed.
PM6Not assessed: no parental testing or family-history data were available to document a presumed de novo occurrence.
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Reasoning
No presumed de novo occurrence is documented because the bundle provides no parental testing, family-history, or proband phenotype information.
Rule
PTEN VCEP PM6: moderate requires an assumed de novo occurrence without confirmed maternity and paternity in a patient with the disease and no family history; strong and very-strong tiers require the specified additional observations or phenotype specificity.
Evidence considered
The PTEN Expert Panel permits PM6 at moderate strength for an assumed de novo occurrence without confirmed maternity and paternity in a patient with the disease and no family history; stronger tiers require multiple occurrences or a qualifying highly specific phenotype.
The consolidated evidence bundle contains no proband-level clinical phenotype, parental genotypes, parentage testing, or family-history information for NM_000314.8:c.775_781del.
Still missing
Obtain parental testing to establish whether the variant is absent in the parents.
Obtain the proband's PTEN-associated phenotype and family history; if maternity and paternity are not confirmed, document the basis for an assumed de novo occurrence.
PP1Not assessed: no pedigree or affected-relative genotype data were available to evaluate co-segregation.
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Reasoning
No pedigree, affected-relative genotypes, phenotypes, or informative meioses are supplied, so co-segregation cannot be evaluated.
Rule
PTEN VCEP PP1: supporting requires 3-4 meioses, moderate 5-6, and strong at least 7 meioses across at least two families, all showing co-segregation with disease in multiple affected relatives.
Evidence considered
The PTEN Expert Panel requires co-segregation in multiple affected family members with 3-4 meioses for PP1 supporting, 5-6 for moderate, and at least 7 across at least two families for strong evidence.
The consolidated evidence bundle contains no pedigree, affected-relative testing, segregation observations, or meiosis count for NM_000314.8:c.775_781del.
Still missing
Provide a pedigree with PTEN-associated phenotypes and variant test results for informative relatives.
Document the number of informative meioses and the number of independent families.
BS2Not assessed: no homozygous observations were available to evaluate presence in healthy individuals.
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Reasoning
BS2 cannot be assessed because no homozygous observations are available; population absence does not establish observation in a healthy or PHTS-unaffected homozygous individual.
Rule
PTEN Expert Panel v3.2 BS2: Strong for a confirmed homozygous healthy/PHTS-unaffected observation (or two if homozygous status is unconfirmed); Supporting for two homozygous observations without clinical data, or when BS1 is also applied.
Evidence considered
gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 direct-variant queries each returned absent; consequently, no homozygote count or associated phenotype is available from these sources.
ClinGen PTEN Expert Panel Specifications v3.2 require observation in the homozygous state in a healthy or PHTS-unaffected individual for BS2 Strong; two homozygous observations without clinical data support BS2 Supporting.
Still missing
Confirmed homozygous observation(s), with health or PHTS-unaffected status where required by the PTEN Expert Panel, are needed to assess BS2.
BS3Not assessed: VCEP BS3 rules (Mighell missense assay, splice assays) do not cover frameshifts, and no variant-specific benign functional study was available.
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Reasoning
The PTEN VCEP BS3 rule (cspec v3.2) is likewise built on the Mighell et al. 2018 (PMID:29706350) missense saturation-mutagenesis phosphatase assay (Cum_score > 0 for supporting-strength benign functional evidence) or, for intronic/synonymous variants, an RNA/mini-gene splicing assay showing no impact. NM_000314.8:c.775_781del is a frameshift, not a missense substitution, so it is not represented in the Mighell dataset, and it is not an intronic or synonymous variant, so the splicing-assay BS3 pathway does not apply. SpliceAI's lack of predicted splice impact is not usable for BS3 because this variant is not a splice-region/intronic/synonymous change contemplated by that rule. No other in vitro/in vivo functional study addressing loss-of-function absence for this specific allele was identified.
Still missing
No BS3-qualifying functional study (phosphatase activity or splicing assay) exists for this frameshift variant under the applicable VCEP framework, which restricts its functional dataset to missense substitutions.
BS4Not assessed: no variant-negative affected relatives were documented, so non-segregation could not be evaluated.
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Reasoning
No affected relative with documented variant-negative status or other non-segregation observation is supplied, so lack of segregation cannot be evaluated.
Rule
PTEN VCEP BS4: supporting requires lack of segregation in affected members of one family; strong requires lack of segregation in affected members of two or more families.
Evidence considered
The PTEN Expert Panel specifies BS4 supporting for lack of segregation in affected members of one family and BS4 strong for lack of segregation in affected members of two or more families.
The consolidated evidence bundle contains no family segregation data or variant results from affected relatives for NM_000314.8:c.775_781del.
Still missing
Provide pedigrees, disease-status assessments, and variant test results for affected relatives.
Establish whether non-segregation occurs in one family or in two or more independent families.
BP2Not assessed: no second pathogenic PTEN variant or phase data were available to evaluate.
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Reasoning
No affected-proband observation with a second pathogenic/likely pathogenic PTEN variant, and no phase data, are present in the case evidence. Therefore the PTEN EP BP2 requirements cannot be evaluated.
Rule
PTEN EP BP2_Supporting: observed in trans with a pathogenic/likely pathogenic PTEN variant, or at least three cis and/or phase-unknown observations with different pathogenic/likely pathogenic PTEN variants.
Evidence considered
The PTEN Expert Panel permits BP2 at supporting strength for a queried variant observed in trans with a pathogenic or likely pathogenic PTEN variant, or after at least three observations in cis and/or with unknown phase with different pathogenic/likely pathogenic PTEN variants.
The consolidated case evidence contains no affected-proband co-variant observation and no cis/trans phase information for NM_000314.8:c.775_781del.
Still missing
Case-level genotypes identifying any second PTEN pathogenic/likely pathogenic variant in the same individual.
Phase evidence showing the queried variant in trans with such a variant, or documentation of at least three independent cis and/or phase-unknown observations with different pathogenic/likely pathogenic PTEN variants.
BP5Not assessed: no data documented an alternate molecular diagnosis explaining the phenotype.
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Reasoning
No affected-case data document an alternate highly penetrant molecular diagnosis with non-overlapping PTEN and alternate-disorder phenotypes.
Rule
PTEN EP BP5 Supporting: at least two cases with an alternate highly penetrant molecular diagnosis and no phenotype overlap with PTEN.
Evidence considered
The PTEN Expert Panel requires at least two such cases; the alternate gene/disorder must be highly penetrant and the patient's personal/family history must show no overlap between that disorder and PTEN. No qualifying cases were supplied.
Still missing
At least two affected cases with an alternate highly penetrant molecular diagnosis and personal/family histories demonstrating no phenotype overlap with PTEN are required.
Not applicable · 12· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: PS1 applies only to missense variants, and this is a 7-bp frameshift deletion with no single amino-acid change.
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Reasoning
NM_000314.8:c.775_781del is a 7-bp frameshifting deletion (NP_000305.3:p.(His259ArgfsTer5)), not a missense substitution. PS1 (same amino acid change as an established pathogenic variant) is defined for missense variants only, per both the PTEN VCEP specification and generic ACMG/AMP; there is no single altered residue/amino-acid-change to compare against a known pathogenic missense variant.
Rule
PTEN VCEP v3.2: PS1 applies to 'Same amino acid change as a previously established pathogenic variant' (missense mechanism) or nucleotide-identical splicing variants; frameshift variants are out of scope.
Evidence considered
case_summary.json normalization confirms protein consequence p.(His259ArgfsTer5), a frameshift, not a missense substitution, so PS1's same-amino-acid-change comparison is not applicable.
PM1N/ANot applicable: PM1 covers missense or in-frame indels in catalytic motifs (residues 90-94, 123-130, 166-168); this frameshift falls outside them.
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Reasoning
PM1 under the PTEN VCEP spec applies to missense variants located in defined catalytic-motif hotspot residues (90-94, 123-130, 166-168 of NP_000305.3), or per VCEP instructions, to in-frame insertions/deletions impacting at least one residue in those catalytic motifs. This variant is a frameshift deletion (p.His259ArgfsTer5), not a missense change and not an in-frame indel, and residue 259 also falls outside the defined catalytic motif ranges. PM1 does not apply.
Rule
PTEN VCEP v3.2 PM1: located in mutational hotspot/catalytic motif residues 90-94, 123-130, 166-168 (missense) or in-frame indels touching those residues.
Evidence considered
PTEN VCEP index guidance states PM1/PM4-adjacent in-frame indel criteria apply only if the variant impacts a residue in one of the specified catalytic motifs (90-94, 123-130, 166-168); c.775_781del is a frameshift (out-of-frame), not an in-frame deletion, and does not touch these motif residues (variant affects residue 259).
PM3VCEPNot applicable: the PTEN Expert Panel designates PM3 not applicable because PTEN hamartoma tumor syndrome is autosomal dominant.
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Reasoning
PM3 is not applicable under the governing ClinGen PTEN Expert Panel specification because PTEN hamartoma tumor syndrome is specified as autosomal dominant and the PTEN EP explicitly states that PM3 is not applicable to PTEN.
VCEP rule
PTEN EP: PM3 not applicable.
Evidence considered
The PTEN Expert Panel framework identifies PTEN hamartoma tumor syndrome as autosomal dominant and states: "This rule is not applicable to PTEN" for PM3.
PM4N/ANot applicable: PM4 requires an in-frame length change or stop-loss; this deletion shifts the reading frame (p.His259ArgfsTer5).
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Reasoning
PM4 under the PTEN VCEP specification applies to protein length changes from in-frame insertions/deletions in a non-repeat region or stop-loss variants. NM_000314.8:c.775_781del is a 7-bp deletion that shifts the reading frame (p.His259ArgfsTer5), producing a frameshifted/truncated protein rather than an in-frame length change, and it is not a stop-loss variant. PM4 is therefore not applicable to this variant class; the loss-of-function consequence is already captured under PVS1.
Rule
PTEN VCEP PM4 requires in-frame indel or stop-loss; variant is frameshift -> not applicable
Evidence considered
PTEN VCEP PM4 rule text restricts applicability to in-frame indels in a non-repeat region or stop-loss variants; this variant is a frameshift deletion, not an in-frame indel or stop-loss.
pvs1_variant_assessment.json confirms consequence_class as frameshift (7 bp deletion, not a multiple of 3), consistent with reading-frame disruption rather than an in-frame protein length change.
PM5N/ANot applicable: PM5 compares missense substitutions at the same residue; this frameshift produces no single amino-acid change.
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Reasoning
PM5 requires the variant under interrogation to be a missense change at a residue where a different missense change has been established pathogenic/likely pathogenic, with BLOSUM62 comparison. c.775_781del produces a frameshift (p.His259ArgfsTer5), not a missense substitution, so there is no amino-acid substitution to compare via BLOSUM62 against other missense variants at codon 259. PM5 is not applicable.
Rule
PTEN VCEP v3.2 PM5: missense change at a residue with a different pathogenic/LP missense change and BLOSUM62 score <= known variant.
Evidence considered
case_summary.json protein consequence is a frameshift (His259ArgfsTer5), which precludes the missense-to-missense BLOSUM62 comparison required by the PTEN VCEP PM5 rule.
PP2N/ANot applicable: PP2 applies to missense variants, and this is a frameshift deletion.
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Reasoning
PP2 applies to missense variants in genes with low rates of benign missense variation where missense is a common disease mechanism. c.775_781del is a frameshift deletion, not a missense variant, so PP2 does not apply regardless of PTEN's missense constraint profile.
Rule
PTEN VCEP v3.2 PP2: missense variant in a gene with low benign missense rate and missense as a common disease mechanism.
Evidence considered
Variant consequence is frameshift (p.His259ArgfsTer5) per case_summary.json normalization, which is categorically excluded from PP2's missense-variant scope.
PP3N/ANot applicable: VCEP PP3 covers only missense (REVEL) and splice variants; this frameshift is neither, and SpliceAI max delta is 0.037.
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Reasoning
NM_000314.8:c.775_781del is a 7-bp in-frame-region coding deletion producing p.(His259ArgfsTer5), a frameshift variant, not a missense substitution or a canonical splice-site/intronic variant. The PTEN VCEP (cspec v3.2) PP3 rule is scoped explicitly to two variant categories: 'Splicing variants' (concordance of SpliceAI and VarSeak) and 'Missense variants' (REVEL > 0.7). This deletion does not fall into either category, so the VCEP PP3 computational rule does not govern it. SpliceAI was nonetheless queried and shows no significant splice-altering signal (max delta = 0.037, well below any pathogenic threshold), which would not support PP3 even if the splicing pathway were considered applicable. No VarSeak result is present in the bundle, so splice concordance cannot be established in any case.
Rule
PTEN VCEP cspec v3.2 PP3
Evidence considered
PTEN VCEP cspec v3.2 PP3 rule text restricts computational evidence to 'Splicing variants: Concordance of SpliceAI and VarSeak' or 'Missense variants: REVEL score > 0.7'; c.775_781del is neither.
SpliceAI Lookup (source_registry key 'spliceai') for NM_000314.8:c.775_781del: DS_AG=0.008, DS_AL=0.037, DS_DG=0.011, DS_DL=0.001, max delta score=0.037, evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).'
Still missing
Variant type (frameshift deletion) is outside the VCEP's PP3 computational-evidence scope (missense REVEL or splicing SpliceAI+VarSeak concordance); no applicable computational pathogenicity code exists for this variant class under this criterion.
No VarSeak splicing prediction present in the evidence bundle even if the splicing pathway were considered.
BP1VCEPNot applicable: the PTEN VCEP marks BP1 not applicable, and this is a frameshift, not a missense variant.
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Reasoning
The PTEN VCEP specification explicitly designates BP1 as Not Applicable for this gene (no missense-tolerant threshold defined). Additionally, this variant is a frameshift, not a missense change, so BP1 (missense variant in a gene where truncating variants are the primary disease mechanism) would not apply on variant-type grounds even under a generic framework.
VCEP rule
PTEN VCEP v3.2: BP1 marked Not Applicable.
Evidence considered
PTEN VCEP v3.2 cspec explicitly flags BP1 as 'Not Applicable' for this gene; independently, the frameshift consequence of c.775_781del places it outside BP1's missense scope.
BP3VCEPNot applicable: the PTEN VCEP marks BP3 not applicable, and this is a frameshift, not an in-frame indel.
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Reasoning
The PTEN VCEP specification (CSPEC v3.2) explicitly marks BP3 as Not Applicable for this gene. In addition, BP3 (in-frame indels in a repeat region/non-critical region with no functional impact) does not apply to this variant on structural grounds since c.775_781del is a frameshift deletion, not an in-frame indel.
VCEP rule
PTEN VCEP CSPEC v3.2: BP3 applicability = Not Applicable
Evidence considered
CSPEC v3.2 for PTEN lists BP3 with applicability: Not Applicable, so this criterion is excluded from the PTEN VCEP framework regardless of variant type.
BP4N/ANot applicable: VCEP BP4 covers only missense and splice variants; this frameshift deletion is neither.
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Reasoning
Same variant-type mismatch as PP3: c.775_781del is a coding frameshift deletion, not a missense variant (no REVEL applicable) and not a splice-site/intronic variant subject to the VCEP's SpliceAI+VarSeak concordance rule. The PTEN VCEP BP4 rule (cspec v3.2) is scoped identically to the PP3 rule and does not extend to frameshift/indel variants. SpliceAI's low delta scores (max 0.037) are consistent with no splicing disruption, but this observation cannot be used to invoke BP4 because the variant does not meet the VCEP's definitional category for the splicing sub-path, and applying it here would risk being interpreted as computational evidence duplicating the frameshift/PVS1 mechanism rather than an independent splicing assessment.
Rule
PTEN VCEP cspec v3.2 BP4
Evidence considered
PTEN VCEP cspec v3.2 BP4 rule text restricts computational evidence to 'Splicing variants: Concordance of SpliceAI and VarSeak' or 'Missense variants: REVEL scores < 0.5'; c.775_781del is neither.
SpliceAI Lookup (source_registry key 'spliceai') for NM_000314.8:c.775_781del: max delta score=0.037, evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).'
Still missing
Variant type (frameshift deletion) is outside the VCEP's BP4 computational-evidence scope (missense REVEL or splicing SpliceAI+VarSeak concordance); no applicable benign computational code exists for this variant class under this criterion.
No VarSeak splicing prediction present in the evidence bundle even if the splicing pathway were considered.
BP7N/ANot applicable: BP7 applies only to synonymous or deep-intronic variants, and this is a coding frameshift deletion.
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Reasoning
BP7 (PTEN VCEP cspec v3.2) applies only to synonymous (silent) variants or intronic variants at or beyond +7/-21 for which splicing predictors show no impact. NM_000314.8:c.775_781del is a coding 7-bp deletion causing a frameshift (p.His259ArgfsTer5), not a synonymous or deep-intronic variant, so BP7 does not apply regardless of the (benign) SpliceAI signal.
Rule
PTEN VCEP cspec v3.2 BP7
Evidence considered
PTEN VCEP cspec v3.2 BP7 rule: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact...' — c.775_781del is a coding frameshift deletion, not synonymous or intronic.
Still missing
Variant is not synonymous or intronic and therefore falls outside BP7's defined 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 -84 bp
0.037
SpliceAI acceptor gainat -195 bp
0.008
SpliceAI donor lossat +28 bp
0.001
SpliceAI donor gainat -159 bp
0.011
Pangolin splice lossmagnitude shown
-0.053
Pangolin splice gain
0.004
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3N/ANot applicable: VCEP PP3 covers only missense (REVEL) and splice variants; this frameshift is neither, and SpliceAI max delta is 0.037.
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Reasoning
NM_000314.8:c.775_781del is a 7-bp in-frame-region coding deletion producing p.(His259ArgfsTer5), a frameshift variant, not a missense substitution or a canonical splice-site/intronic variant. The PTEN VCEP (cspec v3.2) PP3 rule is scoped explicitly to two variant categories: 'Splicing variants' (concordance of SpliceAI and VarSeak) and 'Missense variants' (REVEL > 0.7). This deletion does not fall into either category, so the VCEP PP3 computational rule does not govern it. SpliceAI was nonetheless queried and shows no significant splice-altering signal (max delta = 0.037, well below any pathogenic threshold), which would not support PP3 even if the splicing pathway were considered applicable. No VarSeak result is present in the bundle, so splice concordance cannot be established in any case.
Rule
PTEN VCEP cspec v3.2 PP3
Evidence considered
PTEN VCEP cspec v3.2 PP3 rule text restricts computational evidence to 'Splicing variants: Concordance of SpliceAI and VarSeak' or 'Missense variants: REVEL score > 0.7'; c.775_781del is neither.
SpliceAI Lookup (source_registry key 'spliceai') for NM_000314.8:c.775_781del: DS_AG=0.008, DS_AL=0.037, DS_DG=0.011, DS_DL=0.001, max delta score=0.037, evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).'
Still missing
Variant type (frameshift deletion) is outside the VCEP's PP3 computational-evidence scope (missense REVEL or splicing SpliceAI+VarSeak concordance); no applicable computational pathogenicity code exists for this variant class under this criterion.
No VarSeak splicing prediction present in the evidence bundle even if the splicing pathway were considered.
BP4N/ANot applicable: VCEP BP4 covers only missense and splice variants; this frameshift deletion is neither.
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Reasoning
Same variant-type mismatch as PP3: c.775_781del is a coding frameshift deletion, not a missense variant (no REVEL applicable) and not a splice-site/intronic variant subject to the VCEP's SpliceAI+VarSeak concordance rule. The PTEN VCEP BP4 rule (cspec v3.2) is scoped identically to the PP3 rule and does not extend to frameshift/indel variants. SpliceAI's low delta scores (max 0.037) are consistent with no splicing disruption, but this observation cannot be used to invoke BP4 because the variant does not meet the VCEP's definitional category for the splicing sub-path, and applying it here would risk being interpreted as computational evidence duplicating the frameshift/PVS1 mechanism rather than an independent splicing assessment.
Rule
PTEN VCEP cspec v3.2 BP4
Evidence considered
PTEN VCEP cspec v3.2 BP4 rule text restricts computational evidence to 'Splicing variants: Concordance of SpliceAI and VarSeak' or 'Missense variants: REVEL scores < 0.5'; c.775_781del is neither.
SpliceAI Lookup (source_registry key 'spliceai') for NM_000314.8:c.775_781del: max delta score=0.037, evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).'
Still missing
Variant type (frameshift deletion) is outside the VCEP's BP4 computational-evidence scope (missense REVEL or splicing SpliceAI+VarSeak concordance); no applicable benign computational code exists for this variant class under this criterion.
No VarSeak splicing prediction present in the evidence bundle even if the splicing pathway were considered.
BP7N/ANot applicable: BP7 applies only to synonymous or deep-intronic variants, and this is a coding frameshift deletion.
Details ▾Hide ▴
Reasoning
BP7 (PTEN VCEP cspec v3.2) applies only to synonymous (silent) variants or intronic variants at or beyond +7/-21 for which splicing predictors show no impact. NM_000314.8:c.775_781del is a coding 7-bp deletion causing a frameshift (p.His259ArgfsTer5), not a synonymous or deep-intronic variant, so BP7 does not apply regardless of the (benign) SpliceAI signal.
Rule
PTEN VCEP cspec v3.2 BP7
Evidence considered
PTEN VCEP cspec v3.2 BP7 rule: 'A synonymous (silent) or intronic variant at or beyond +7/-21 for which splicing prediction algorithms predict no impact...' — c.775_781del is a coding frameshift deletion, not synonymous or intronic.
Still missing
Variant is not synonymous or intronic and therefore falls outside BP7's defined 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 7.1.5.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.