Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
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.
About TERT
TERT encodes the catalytic subunit of telomerase, the enzyme that maintains chromosome ends (telomeres) by adding TTAGGG repeat sequences and preserves genomic integrity. Telomerase is normally switched off in adult somatic cells, so telomeres shorten with each cell division, contributing to cellular senescence; reactivation of telomerase can therefore help cells divide indefinitely. Telomerase activity is upregulated in the vast majority of tumors and is thought to drive cancer cell immortality, and TERT alterations — including promoter mutations and gene amplification — are found in cancers such as melanoma, liver, bladder, and brain tumors.
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Double-check every criterion and its underlying evidence
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01The reasoning
How it was classified
The recorded framework is Not recorded. 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 (Supporting): highest observed allele frequency 0.0275% (gnomAD v4.1 NFE) is ~3.6x below the 0.1% ceiling, with zero homozygotes.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Met (Supporting): SpliceAI max delta 0.011 is below the 0.1 threshold, predicting no impact on splicing for this synonymous variant.
Recorded classification: Uncertain significance
Variant of Uncertain Significance: one supporting pathogenic (PM2, gnomAD AF 0.0275%) and one supporting benign (BP4, SpliceAI 0.011) criterion form a conflicting combination matching no classification rule.
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
329 / 1,614,008 alleles
gnomAD v4.1: 329 / 1,614,008 alleles. Recorded AF 0.00020384. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.78505e-05; MAF= 0.00279%, 7/251342 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.15991e-05; MAF= 0.00616%, 7/113638 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 12 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Framework: generic ACMG/AMP 2015 (Richards et al., PMID:25741868) is the governing specification — no TERT VCEP/CSPEC exists (vcep_materials.json reports 'no cspec url available', framework_mode=generic_acmg_fallback).
PS2 (de novo, parentage confirmed): not_assessed — no proband de novo occurrence or parental-testing data in any source; no publication mentions the variant.
PM6 (assumed de novo, unconfirmed): not_assessed — no proband-level de novo observation reported anywhere.
PP1 (co-segregation): not_assessed — no family/pedigree segregation data, no meioses observable in the case evidence.
BS4 (non-segregation): not_assessed — no affected family member tested and found negative for the variant; absence of data is not evidence of non-segregation.
This group contributes no positive or negative evidence to the classification. The ClinVar Likely benign label and gnomAD allele frequency are adjudicated by other criterion groups and were deliberately not used to infer any de novo/segregation outcome here.
Framework: generic ACMG/AMP 2015 (Richards et al., PMID:25741868) is the governing specification — no TERT VCEP/CSPEC exists (vcep_materials.json reports 'no cspec url available', framework_mode=generic_acmg_fallback, precedence_rank 3).
Variant context: NM_198253.2:c.2283C>T is a synonymous change, p.(Ser761=), in exon 6 of TERT; functional impact could only arise via splicing or other regulatory effects, which no source in the bundle assays.
PS3 (well-established functional studies show deleterious effect): not_assessed — no functional assay evidence in the bundle; all 4 candidate PMIDs are gene reviews/PDQ summaries or a methods paper, none reporting functional studies of this variant; fulltext_map.json is empty.
BS3 (well-established functional studies show no damaging effect): not_assessed — no functional study exists for this variant; SpliceAI (max delta 0.011) and OncoKB ('Unknown Oncogenic Effect', non-variant-specific) were consulted and documented but are in silico/non-variant-specific and were not used to satisfy BS3.
This group contributes no positive or negative functional evidence to the classification; gnomAD allele frequency and ClinVar Likely benign status are adjudicated by other criterion groups.
Governing framework: no TERT ClinGen CSPEC/VCEP specification exists (cspec found=false; vcep_materials.json empty; final_classification_framework.json source=generic_acmg_fallback), so generic ACMG/AMP 2015 (PMID:25741868) governs this case.
PS4: not assessed — no case-control or cohort study for TERT c.2283C>T exists in the case bundle; the PS4 literature screen passed 0 papers and the retrieved PMIDs do not mention the variant.
PP4: not assessed — the case bundle contains no proband phenotype or family-history data with which to evaluate phenotype specificity.
PP5: not met — ClinVar variation 471859 has no expert-panel classification (expert_panel_submissions=0); the three clinical-laboratory 'Likely benign' submissions are non-expert assertions that cannot trigger PP5.
BP5: not assessed — no case-level evidence of an alternate molecular basis for disease is present in the case bundle.
BP6: not met — the aggregate ClinVar 'Likely benign' label comes from three non-expert clinical laboratories; policy restricts BP6 to exact-variant expert-panel Benign/Likely benign classifications.
Both allelic criteria (PM3, BP2) depend on phase information relative to a pathogenic TERT allele, which is entirely absent from this case: no proband, pedigree, segregation, or phased observations were collected.
No ClinGen CSPEC/VCEP specification exists for TERT, so the generic ACMG/AMP 2015 rules (PMID 25741868) define PM3 and BP2; the variant is a synonymous TERT change (p.(Ser761=)) and no phase-based evidence for either criterion exists in the bundle.
Population data (gnomAD v2.1/v4.1/Canada, 0 homozygotes) and the ClinVar record (3 Likely benign submissions, no phase data) were reviewed and provide no criterion-bearing evidence for PM3 or BP2; neither criterion is inferred from the ClinVar final classification.
PM3 is not categorically inapplicable because autosomal recessive TERT phenotypes exist (e.g., dyskeratosis congenita AR5), but the required trans/biallelic proband observation is missing; BP2 similarly cannot be evaluated without a phased observation.
PP3 not_met: SpliceAI max delta 0.011 is far below the 0.2 splice-altering threshold (Jaganathan et al. 2019, PMID 30661751), predicting no splice impact; no other computational tool provides a damaging prediction; missense predictors (REVEL/BayesDel/aGVGD) are not applicable to this synonymous variant and are absent/unusable in this case.
BP4 met (supporting): the governing generic ACMG/AMP framework (no TERT CSPEC/VCEP exists) pre-assigns BP4 (supporting) for synonymous variants with SpliceAI max delta < 0.1; observed max delta is 0.011.
BP7 not_assessed: synonymous status and absence of predicted splice impact are verified, but no nucleotide conservation score (phyloP/GERP) is available to verify the 'nucleotide is not highly conserved' condition; human review required. The same SpliceAI prediction is already applied under BP4, so BP7 would double-count it under the governing one-mechanism rule.
No ClinGen CSPEC/VCEP specification and no local gene-specific framework exist for TERT, so generic ACMG/AMP 2015 (PMID 25741868) governs this group; the generic_acmg_combination_rules artifact confirms this fallback.
BA1 not met: highest observed AF 0.0275% (NFE, gnomAD v4.1) is far below the 1% operating threshold (and below the 5% BA1 example in Richards et al. 2015).
BS1 not met: highest AF 0.0275% is well below the 0.3% operating threshold, and the frequency does not exceed expectation for the rare, adult-onset TERT-related disorders (DC, IPF).
BS2 not met: 0 homozygotes in all three population datasets, no phenotyped healthy-adult carriers, and TERT-related disorders have adult onset with reduced penetrance, failing BS2's early-onset full-penetrance premise.
PM2 met (supporting): highest population AF 0.0275% is below the 0.1% PM2 ceiling across gnomAD v4.1, v2.1, and gnomAD-Canada, with no homozygotes; applied at supporting strength only.
Population evidence is concordant across three independent datasets (gnomAD v2.1, v4.1, gnomAD-Canada) with no ancestry-specific frequency excess that would alter any decision.
No criteria match.
Met · 2
PM2SupportingMet (Supporting): highest observed allele frequency 0.0275% (gnomAD v4.1 NFE) is ~3.6x below the 0.1% ceiling, with zero homozygotes.
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Reasoning
PM2 is met at supporting strength: the variant is present at extremely low frequency in large, ethnically diverse population cohorts, below the lab's non-VCEP PM2 ceiling of 0.1% using the highest observed population frequency. gnomAD v4.1: total AF 0.0204% (329/1,614,008), NFE AF 0.0275% (324/1,180,054), grpmax FAF 0.0249%; gnomAD v2.1: total AF 0.0028%; gnomAD-Canada: AF 0.0109%. The maximum AF (0.0275%, NFE) is ~3.6x below the 0.1% ceiling, with 0 homozygotes in every dataset. PM2_Supporting applies.
Rule
ACMG/AMP 2015 (PMID 25741868) PM2: absent from controls or at extremely low frequency in large population cohorts if recessive (lab non-VCEP operating ceiling 0.1%; applied at supporting strength)
Evidence considered
gnomAD v4.1 (largest and most current dataset): total AF 0.00020384 (0.0204%, 329/1,614,008 alleles), NFE AF 0.00027456 (0.0275%, 324/1,180,054), grpmax FAF 0.00024924 (0.0249%), homozygotes 0 — highest population frequency 0.0275% is below the 0.1% PM2 ceiling.
gnomAD v2.1: total AF 2.785e-05 (0.00279%, 7/251,342), grpmax FAF 2.856e-05, homozygotes 0 — even lower, consistent with extremely low frequency.
gnomAD-Canada v1.0 (HostSeq): AF 0.00010859 (0.0109%, 2/18,418), homozygotes 0.
Lab non-VCEP gnomAD operating calibration: PM2 < 0.1%; met at supporting strength (PM2 is a supporting-strength criterion in ACMG/AMP 2015, PMID 25741868).
Generic ACMG/AMP 2015 PM2 (PMID 25741868): variant absent or at extremely low frequency in large population cohorts (ESP, 1000 Genomes, ExAC/gnomAD); the observed 0.02-0.03% range qualifies as extremely low for a rare, adult-onset disorder.
Still missing
PM2 relies on the lab's documented non-VCEP operating ceiling (<0.1%); the variant is present rather than absent in gnomAD v4.1 (329 alleles), so PM2 is applied at supporting strength only and should not be upgraded.
BP4SupportingMet (Supporting): SpliceAI max delta 0.011 is below the 0.1 threshold, predicting no impact on splicing for this synonymous variant.
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Reasoning
Governing generic ACMG/AMP framework (registry key 'generic_acmg_combination_rules'; Richards et al. 2015, PMID 25741868) pre-assigns BP4 (supporting) for synonymous/non-missense variants whose SpliceAI max delta is < 0.1 (SVI-recommended thresholds codified in the framework document). SpliceAI max delta for c.2283C>T is 0.011 (< 0.1), predicting no impact on splicing, so BP4 is met at supporting strength. This is the single splice-path prediction applied for this variant per the framework's one-mechanism rule; it is not double-counted into BP7. Missense predictors are not applicable (synonymous variant) and BayesDel is not usable (no verified published threshold).
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868) with lab operating thresholds for non-VCEP cases: BP4 = computational evidence suggests no impact on gene/gene product; for synonymous/non-missense variants use SpliceAI only, max delta < 0.1 -> BP4 (supporting).
Evidence considered
SpliceAI max delta score 0.011 (DS_AG=0.000, DS_AL=0.001, DS_DG=0.002, DS_DL=0.011) is below the 0.1 threshold at which the governing generic framework assigns BP4 (supporting) for synonymous/non-missense variants, and far below the 0.2 splice-altering cutoff from the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751).
Governing framework (registry key 'generic_acmg_combination_rules', source basis Richards et al. 2015, PMID 25741868) operating rule for non-VCEP cases: for intronic/synonymous/non-canonical-splice-position variants use SpliceAI only; SpliceAI max delta < 0.1 -> BP4 (supporting); max delta 0.1-0.2 gray zone (neither met).
REVEL score not found and BayesDel score not found in case data; aGVGD not present. Per the framework's one-mechanism rule, only the splice path is evaluated for this synonymous variant, so the absent missense predictors do not block the BP4 call.
PP3Not met: SpliceAI max delta 0.011 is far below the 0.2 splice-altering cutoff, and no missense predictors apply to this synonymous change.
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Reasoning
No computational evidence supports a deleterious effect. SpliceAI (registry key 'spliceai') reports max delta score 0.011 for NM_198253.2:c.2283C>T (DS_AG=0.000, DS_AL=0.001, DS_DG=0.002, DS_DL=0.011), far below the 0.2 splice-altering cutoff from the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751), so no splice impact and no de novo splice site is predicted. The variant is synonymous (NP_937983.2:p.(Ser761=)), so the missense in-silico path (REVEL/BayesDel/aGVGD) is not applicable; REVEL returned no score and BayesDel returned no score in this case, and BayesDel has no verified published threshold under the governing rule. The governing generic ACMG framework's operating threshold for PP3 (SpliceAI max delta > 0.2, for non-missense variants) is not approached.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868) with lab operating thresholds for non-VCEP cases: PP3 = computational evidence supports a deleterious effect; for synonymous/non-missense variants use SpliceAI only, max delta > 0.2 -> PP3 (supporting); BayesDel never used (no verified threshold).
Evidence considered
SpliceAI lookup (registry key 'spliceai') returns max delta score 0.011 for NM_198253.2:c.2283C>T (DS_AG=0.000, DS_AL=0.001, DS_DG=0.002, DS_DL=0.011), far below the 0.2 splice-altering cutoff recommended in the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751); no significant splice impact and no creation of a new splice site predicted.
Governing framework: no ClinGen CSPEC/VCEP specification exists for TERT (vcep_materials: 'no cspec url available', gene_vcep_dir null; case framework_mode 'generic_acmg'), so generic ACMG/AMP 2015 (Richards et al., PMID 25741868; registry key 'generic_acmg_combination_rules') applies. Its operating in-silico rule for synonymous/non-missense variants uses SpliceAI only, with SVI-recommended thresholds (as codified in the framework document, attributed there to Walker et al. 2023): max delta > 0.2 -> PP3 (supporting), max delta < 0.1 -> BP4 (supporting), 0.1-0.2 gray zone; BayesDel is explicitly excluded because no verified published threshold is available.
Variant is synonymous (NP_937983.2:p.(Ser761=); pvs1_variant_assessment consequence_class 'synonymous', canonical_splice_consensus=false). Per VariantValidator/Mutalyzer exon coordinates in prefetch.json, c.2283 lies in TERT exon 6 (CDS 2131-2286), 3 nucleotides upstream of the exon 6 donor junction, i.e., a non-canonical exonic splice-region position.
REVEL lookup returned no score (evidence.json revel.found=false) and BayesDel lookup returned no score (evidence.json bayesdel.found=false); aGVGD is not present in this case. REVEL and other missense predictors are not applicable to a synonymous substitution, and BayesDel is not usable under the governing rule.
Still missing
No damaging prediction from any computational tool; missense-path predictors (REVEL/BayesDel/aGVGD) are absent in this case, though they are not applicable to a synonymous variant and their absence does not change the PP3 outcome.
PP5Not met: no ClinVar expert-panel pathogenic assertion exists; only three ordinary laboratory submissions, all Likely benign.
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Reasoning
Under governing policy, PP5 may be triggered only by an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation 471859 has expert_panel_submissions = 0: all three submissions are ordinary clinical laboratories (Labcorp Genetics/Invitae, Ambry Genetics, PreventionGenetics), all classified Likely benign, with 'criteria provided, single submitter' or 'no assertion criteria provided' review status. No expert-panel pathogenic assertion exists for this variant, and ordinary laboratory submissions and aggregate ClinVar labels must never trigger PP5. Therefore PP5 is not met.
Rule
policy_restricted: pp5 only for exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification; non-expert submissions never trigger
Evidence considered
ClinVar variation 471859: expert_panel_submissions = 0; all 3 submissions are clinical laboratories (Labcorp Genetics/Invitae SCV000650740, Ambry Genetics SCV002732269, PreventionGenetics SCV004769630) with Likely benign classifications; review stars = 2 (criteria provided, multiple submitters, no conflicts).
Per governing policy, PP5 applies only for an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification; non-expert laboratory submissions and aggregate labels are excluded.
The three candidate papers triaged for PP5 (20301779, 26389258, 26389333) do not mention this variant and carry no pathogenic assertion for it.
BA1Not met: highest allele frequency 0.0275% is 36x below the 1% stand-alone benign threshold.
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Reasoning
BA1 requires an allele frequency far too high to be consistent with disease causation (stand-alone benign, typically AF >5% in ACMG/AMP 2015, or >1% under the lab's non-VCEP gnomAD operating calibration). The highest observed frequency for NM_198253.2:c.2283C>T (p.Ser761=) is 0.0275% (324/1,180,054 alleles in European non-Finnish, gnomAD v4.1); total gnomAD v4.1 AF is 0.0204% (329/1,614,008), gnomAD v2.1 AF is 0.0028% (7/251,342), and gnomAD-Canada AF is 0.0109% (2/18,418). All frequencies are 36-350x below the 1% operating threshold, so BA1 is clearly not met.
Rule
ACMG/AMP 2015 (PMID 25741868) BA1: allele frequency in a reference population is too high to be consistent with disease causation (stand-alone benign, e.g. AF >5%; lab non-VCEP operating threshold 1%)
Evidence considered
gnomAD v4.1 (GRCh38, joint exome+genome): total AF 0.0204% (329/1,614,008 alleles), NFE AF 0.0275% (324/1,180,054), grpmax FAF 0.0249% (0.00024924), homozygotes 0; highest population frequency is the NFE subpopulation.
gnomAD v2.1 (GRCh37, exome): total AF 0.00279% (7/251,342 alleles), NFE AF 0.00616% (7/113,638), grpmax FAF 0.00286%, homozygotes 0.
gnomAD-Canada v1.0 (HostSeq genomes): AF 0.0109% (2/18,418 alleles), homozygotes 0.
Lab non-VCEP gnomAD operating calibration for generic ACMG population criteria: BA1 > 1%, BS1 > 0.3%, PM2 < 0.1%; highest observed AF (0.0275%) is far below the BA1 threshold, and below any reasonable BA1 interpretation (including the 5% example in Richards et al. 2015, PMID 25741868).
No ClinGen CSPEC/VCEP or local gene-specific framework exists for TERT (vcep_materials.json: 'no cspec url available'; final_classification_framework found: false), so generic ACMG/AMP 2015 (PMID 25741868) applies via generic_acmg_combination_rules.
BS1Not met: highest allele frequency 0.0275% is ~11x below the 0.3% threshold for frequencies exceeding disease expectation.
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Reasoning
BS1 requires an allele frequency greater than expected for the disorder (lab non-VCEP operating threshold >0.3%). TERT-related disorders (dyskeratosis congenita, autosomal dominant; idiopathic pulmonary fibrosis; TERT-related disorder) are rare, adult-onset conditions. The maximum observed allele frequency is 0.0275% (NFE, gnomAD v4.1), roughly 11x below the 0.3% operating threshold and far below what would exceed expectation for these rare disorders. BS1 is not met.
Rule
ACMG/AMP 2015 (PMID 25741868) BS1: allele frequency is greater than expected for the disorder (lab non-VCEP operating threshold 0.3%)
Evidence considered
gnomAD v4.1: NFE AF 0.0275% (324/1,180,054) is the highest population frequency observed; total AF 0.0204%; grpmax FAF 0.0249%; all below the 0.3% BS1 operating threshold.
gnomAD v2.1: total AF 0.00279%, NFE AF 0.00616%; gnomAD-Canada v1.0: AF 0.0109% (2/18,418); all far below the BS1 threshold.
Disease context from ClinVar variation 471859 conditions field (used for disease-prevalence/penetrance context only, not its Likely benign classification): 'Dyskeratosis congenita', 'Dyskeratosis congenita, autosomal dominant 2', 'Idiopathic Pulmonary Fibrosis', 'TERT-related disorder' — rare, adult-onset telomere biology disorders; a 0.0275% frequency does not exceed expectation for these conditions.
Lab non-VCEP gnomAD operating calibration: BS1 > 0.3%; highest observed AF 0.0275% does not reach the threshold, so BS1 not met.
Generic ACMG/AMP 2015 framework (PMID 25741868) applies because no CSPEC/VCEP or local gene-specific framework exists for TERT.
BS2Not met: no homozygotes are observed in any population cohort, and TERT disorders are adult-onset with incomplete penetrance.
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Reasoning
BS2 requires observation of the variant in healthy adult individuals, with full penetrance expected at an early age (homozygous for a recessive disorder, or heterozygous for a dominant disorder with early-onset full penetrance). The variant is present only as heterozygous carriers in unselected general-population cohorts (gnomAD v2.1: 7 alleles, 0 homozygotes; gnomAD v4.1: 329 alleles, 0 homozygotes; gnomAD-Canada: 2 alleles, 0 homozygotes). No homozygotes are observed, and TERT-related disorders are adult-onset with reduced/incomplete penetrance, so carrier presence in unselected population databases does not satisfy the 'healthy adult, full penetrance expected at early age' requirement. BS2 is not met.
Rule
ACMG/AMP 2015 (PMID 25741868) BS2: observed in a healthy adult individual for a recessive (homozygous), autosomal dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age
Disease context from ClinVar variation 471859 conditions field (used for penetrance model only, not its Likely benign classification): dyskeratosis congenita (AD), idiopathic pulmonary fibrosis, TERT-related disorder — adult-onset conditions with reduced/incomplete penetrance, so observing heterozygous carriers in an unselected cohort does not establish BS2.
Generic ACMG/AMP 2015 BS2 (PMID 25741868) requires observation in healthy adults where full penetrance is expected at an early age; this premise is not met for TERT-related telomere biology disorders.
No dedicated unaffected-carrier (e.g., case-control or family-based phenotyped) dataset for this variant was present in the evidence bundle.
Still missing
No phenotyped healthy-adult cohort data for TERT-related disorders (dyskeratosis congenita, IPF) was available to assess unaffected adult carriers; gnomAD is an unselected general-population resource without phenotype-based exclusion of adult-onset telomere biology disorders.
No homozygous carriers observed in any dataset, so the recessive BS2 route cannot be evaluated either.
BP6Not met: no ClinVar expert-panel benign classification exists; the Likely benign label comes only from ordinary laboratory submissions.
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Reasoning
Under governing policy, BP6 may be triggered only by an exact-variant ClinVar expert-panel classification of Benign or Likely benign. Although ClinVar variation 471859 carries an aggregate 'Likely benign' label, it derives exclusively from three ordinary clinical-laboratory submissions (Labcorp Genetics/Invitae, Ambry Genetics, PreventionGenetics) with expert_panel_submissions = 0. Ordinary laboratory submissions and aggregate ClinVar labels must never trigger BP6. Therefore BP6 is not met.
Rule
policy_restricted: bp6 only for exact-variant ClinVar expert-panel Benign/Likely benign classification; non-expert submissions never trigger
Evidence considered
ClinVar variation 471859 aggregate label 'Likely benign' (3 clinical laboratories) is not an expert-panel classification; expert_panel_submissions = 0 and review stars = 2.
Per governing policy, BP6 applies only for an exact-variant ClinVar expert-panel Benign/Likely benign classification; non-expert laboratory submissions and aggregate labels are excluded.
PS2Not assessed: no proband or parental genotype data exist to evaluate a de novo occurrence with confirmed parentage.
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Reasoning
No evidence of a de novo occurrence with confirmed parentage exists anywhere in the case bundle. The ClinVar record (VCV000471859, 3 germline submissions, all Likely benign) contains no proband genotype, no parental-testing results, and no family-history note. All 4 candidate publications were triaged with variant_mentioned=false, and fulltext_map.json is empty, so no publication reports this variant in a proband with confirmed parental genotypes. Without proband/parental genotype data, PS2 cannot be evaluated.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID:25741868): PS2 = de novo (both maternity and paternity confirmed) in a patient with the disease and no family history (strong evidence of pathogenicity).
Evidence considered
Governing framework: no TERT VCEP/CSPEC specification exists (vcep_materials.json: 'no cspec url available'; framework_mode=generic_acmg_fallback, precedence_rank 3), so generic ACMG/AMP 2015 criteria (Richards et al., PMID:25741868) apply: PS2 = de novo with both maternity and paternity confirmed, in a patient with the disease and no family history.
Searched the entire case-evidence bundle (review_manifest, case_summary, source_registry, prefetch, evidence, literature_pass, vcep_materials, fulltext_map) for de novo/proband/parental-testing terms: zero matches.
ClinVar record VCV000471859 (clinvar): 3 germline submissions (Labcorp/Invitae SCV000650740, Ambry SCV002732269, PreventionGenetics SCV004769630), all Likely benign; record contains no proband genotype, no parental-testing, and no pedigree/segregation information; conditions listed are Dyskeratosis congenita, DC autosomal dominant 2, Idiopathic Pulmonary Fibrosis, TERT-related disorder.
Literature triage (literature_pass.json, publications.json): all 4 candidate PMIDs (20301779, 26389258, 26389333, 28492532) have variant_mentioned=false; none provide de novo or parental-genotype data for c.2283C>T.
No full text available for any publication (fulltext_map.json is empty {}); publications directory contains only gene-review/PDQ screenshots, none mentioning this variant.
No other source (gnomad_v2, gnomad_v4, gnomad_canada, oncokb, spliceai) contains any de novo or family-based evidence.
Still missing
No proband de novo occurrence data for c.2283C>T (p.Ser761=)
No parental testing results (maternity and paternity confirmation) in any source
No proband phenotype/family-history information is provided in this case bundle
PS3Not assessed: no functional assay (e.g., telomerase activity or splicing/minigene analysis) for this exact variant was available.
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Reasoning
No well-established functional study demonstrating a deleterious effect of c.2283C>T (p.Ser761=) exists anywhere in the case bundle. The variant is a synonymous change in exon 6 of TERT (telomerase reverse transcriptase), so a functional effect could only arise through splicing or other regulatory mechanisms, and PS3 would require a validated assay (e.g., telomerase activity/telomere-length assay or RNA/splicing/minigene analysis with appropriate controls and biological relevance to telomere biology disorders) for this exact variant — none is present. In silico predictors (SpliceAI max delta 0.011) and non-variant-specific annotations (OncoKB 'Unknown Oncogenic Effect', is_variant_specific=false) do not constitute functional studies. PS3 is therefore not assessed pending functional assay data.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID:25741868): PS3 = well-established functional studies show a deleterious effect (strong evidence of pathogenicity).
Evidence considered
Governing framework: no TERT VCEP/CSPEC exists (vcep_materials.json: 'no cspec url available', gene_vcep_dir null, final_classification_framework = generic_acmg_fallback, precedence_rank 3), so generic ACMG/AMP 2015 (Richards et al., PMID:25741868) definitions apply: PS3 = well-established functional studies show a deleterious effect (strong evidence of pathogenicity).
Screened the entire case-evidence bundle (review_manifest, case_summary, source_registry, prefetch, evidence, literature_pass, vcep_materials, fulltext_map) and the publications directory for functional assay data on c.2283C>T (p.Ser761=): no functional study of any kind is present.
Literature pass (literature_pass.json): the 4 candidate PMIDs (20301779 GeneReviews Dyskeratosis Congenita; 26389258 and 26389333 PDQ reviews; 28492532 Sherloc classification-methods paper) are reviews/background, not functional studies of this variant; fulltext_map.json is empty and the publications directory holds only PDQ/GeneReviews page screenshots.
OncoKB (oncokb) entry for TERT/S761= reports 'Unknown Oncogenic Effect' with is_variant_specific=false — no variant-specific functional or oncogenicity data; not usable as functional assay evidence for PS3.
ClinVar Likely benign labels (clinvar), gnomAD allele frequencies (gnomad_v2, gnomad_v4, gnomad_canada), and COSMIC somatic occurrence n=1 (cosmic) are not functional assay evidence and were not used for PS3.
Still missing
No functional assay data for this exact variant in any bundle source; a targeted literature search for functional studies of TERT c.2283C>T (p.Ser761=) (telomerase activity, telomere length, RNA/splicing/minigene assays) would be required to assess PS3
No publication in the case reports any functional study of this variant; fulltext_map.json is empty, so no assay descriptions could be screened
PS4Not assessed: no case-control or cohort prevalence data exist for this variant; the single COSMIC occurrence is somatic, not germline.
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Reasoning
PS4 (Richards et al. 2015, PMID:25741868) requires the prevalence of the variant in affected individuals to be significantly increased compared with controls in a case-control or cohort study. No such study exists for NM_198253.2:c.2283C>T (TERT, p.Ser761=) in the case bundle: the PS4 literature screen (screen_PS4.json) screened 0 papers and passed none; the four PMIDs retrieved from ClinVar (20301779, 26389258, 26389333, 28492532) do not mention this exact variant and contain no case-control prevalence data. COSMIC reports one somatic occurrence (COSV57215940), which is somatic cancer data and does not constitute germline case-control enrichment. General-population frequencies (gnomAD v2.1 AF 0.00279%, gnomAD v4.1 AF 0.0204%, gnomAD-Canada AF 0.0109%) are not case-control evidence. Because the evidence required to evaluate PS4 is absent, the criterion is not assessed.
Rule
generic_acmg_2015: ps4 = prevalence in affected individuals significantly increased vs controls (PMID:25741868); requires case-control/cohort data
Evidence considered
No case-control or cohort study for TERT c.2283C>T (p.Ser761=) is present in the case bundle; screen_PS4.json screened 0 papers and passed 0.
The four PMIDs retrieved from ClinVar (20301779, 26389258, 26389333, 28492532) do not mention this variant (variant_mentioned=false in publications.json) and provide no case-control prevalence data.
COSMIC lists a single somatic occurrence (COSV57215940, n=1); somatic cancer data is not germline case-control enrichment and does not satisfy PS4.
gnomAD v2.1 (AF 2.785e-05), gnomAD v4.1 (AF 2.038e-04) and gnomAD-Canada (AF 1.086e-04) are general-population frequencies, not affected-vs-control enrichment data.
Still missing
No case-control or cohort study for this exact variant (TERT c.2283C>T / p.Ser761=) is available; PS4 cannot be evaluated without one.
PM3Not assessed: no proband, pedigree, or phase data exist to evaluate trans configuration with a pathogenic allele.
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Reasoning
PM3 (Richards et al. 2015, PMID 25741868) requires a proband observation of the variant in trans with a pathogenic (or likely pathogenic) variant on the other allele, or biallelic/homozygous occurrence, for a recessive phenotype. The case bundle contains no proband, pedigree, segregation, or phase data of any kind: no trans-configuration with a pathogenic TERT variant is reported, no compound-heterozygous or homozygous proband observation exists, and no literature source in this case mentions the variant at all. gnomAD v2.1/v4.1/gnomAD-Canada report 0 homozygotes, but population homozygosity counts are not proband phase evidence and cannot substitute for an observed trans configuration. ClinVar (variation 471859) carries three Likely benign clinical-laboratory submissions with no case-level phase observations; the record's final classification is not used to infer any criterion. TERT-related telomere biology disorders are predominantly autosomal dominant (e.g., dyskeratosis congenita AD2, pulmonary fibrosis), but autosomal recessive forms exist, so PM3 is not categorically inapplicable; it simply cannot be evaluated with the evidence available. Status set to not_assessed pending proband/phase data.
Rule
PM3: For recessive disorders, detected in trans with a pathogenic variant (Richards et al. 2015, PMID 25741868).
Evidence considered
Generic ACMG/AMP 2015 framework (PMID 25741868) governs because no ClinGen CSPEC/VCEP specification exists for TERT (cspec found=false; vcep_materials empty); PM3 requires the variant detected in trans with a pathogenic variant for a recessive disorder.
ClinVar variation 471859 (3 clinical-laboratory submissions, all Likely benign) contains no case-level phase, trans/cis, or proband observations; no criteria are inferred from the record's final classification.
gnomAD v2.1 (7/251342 alleles), gnomAD v4.1 (329/1614008 alleles), and gnomAD-Canada v1.0 (2/18418 alleles) all report 0 homozygotes for this variant; population homozygosity data does not constitute proband phase evidence for PM3.
Literature indexed for this case (PMIDs 20301779, 26389258, 26389333, 28492532) was checked via the literature pass: none is a case report of c.2283C>T and none provides trans-phase or biallelic observations of this variant; fulltext_map.json is empty (no full text available).
Still missing
No proband or family pedigree data is available; need phase determination (trans vs cis) of c.2283C>T relative to any pathogenic TERT variant in an affected proband.
No evidence of biallelic (homozygous or compound heterozygous) occurrence of this variant in an affected individual.
No literature reports this specific variant in a recessive TERT phenotype; confirm the inheritance mode (AD vs AR) relevant to the proband's phenotype.
PM6Not assessed: no source reports an assumed (unconfirmed) de novo occurrence of this variant.
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Reasoning
No source reports an assumed de novo occurrence (without parental confirmation) for this variant. ClinVar submissions carry no assertion of de novo origin, and no publication mentioning the variant exists (variant_mentioned=false for all 4 triaged PMIDs; fulltext_map empty). PM6 cannot be evaluated without a proband report of de novo occurrence, even unconfirmed.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID:25741868): PM6 = assumed de novo, but without confirmation of parentage (moderate evidence of pathogenicity).
Evidence considered
Governing framework: generic ACMG/AMP 2015 (Richards et al., PMID:25741868) because no TERT VCEP/CSPEC exists (vcep_materials.json: 'no cspec url available'); PM6 = assumed de novo, without confirmation of parentage (moderate evidence of pathogenicity).
Searched the case-evidence bundle and all publication metadata for de novo/assumed-de-novo statements: none found.
ClinVar record (clinvar) submissions are all germline-origin Likely benign with no de novo assertion and no family testing information.
Literature pass (literature_pass.json) triaged papers by theme including case_observation and segregation; none of the 4 PMIDs were flagged for de novo/segregation content, and all have variant_mentioned=false.
Still missing
No report of assumed de novo occurrence without parental confirmation
No proband-level observation data for c.2283C>T in any source
No proband phenotype or segregation context provided in this case bundle
PP1Not assessed: no family or pedigree testing exists, so zero informative meioses can be counted.
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Reasoning
No co-segregation data exist for this variant: no family/pedigree testing is described in ClinVar, no publication mentions the variant, and fulltext_map.json is empty. Zero meioses or affected relatives segregating the variant can be counted. PP1 cannot be evaluated.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID:25741868): PP1 = co-segregation with disease in affected family members (supporting evidence of pathogenicity).
Evidence considered
Governing framework: generic ACMG/AMP 2015 (Richards et al., PMID:25741868) because no TERT VCEP/CSPEC exists (vcep_materials.json: 'no cspec url available'); PP1 = co-segregation with disease in affected family members (supporting evidence of pathogenicity).
Searched the case-evidence bundle for segregation/meioses/affected-relative terms: zero matches.
ClinVar record (clinvar) VCV000471859 contains no family/pedigree or segregation data across its 3 submissions.
Literature pass (literature_pass.json) note states papers were triaged by theme including segregation, but no PP1/segregation candidates were surfaced; all 4 PMIDs have variant_mentioned=false and fulltext_map.json is empty (no full text).
No population or functional source (gnomad_v2, gnomad_v4, gnomad_canada, oncokb, spliceai) provides segregation information.
Still missing
No segregation studies of c.2283C>T in affected family members
No pedigree or meioses data in any source
No affected-relative genotype information available
PP4Not assessed: no proband phenotype or family-history information exists to evaluate disease specificity.
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Reasoning
PP4 (Richards et al. 2015, PMID:25741868) requires a phenotype or family history that is highly specific for a disease with a single genetic etiology. The case bundle contains no proband phenotype, family history, or clinical description data whatsoever (case_summary.json, evidence.json, and the manifest contain variant-centric data only). Without any case-level phenotypic information, phenotype specificity for a TERT-related telomere biology disorder cannot be evaluated, so the criterion is not assessed.
Rule
generic_acmg_2015: pp4 = phenotype or family history highly specific for disease with single genetic etiology (PMID:25741868); requires case-level clinical data
Evidence considered
No proband phenotype, family history, or clinical description is available anywhere in the case bundle; PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology.
Still missing
No proband phenotype or family-history data is present in the case bundle; PP4 cannot be evaluated without a clinical description of the affected individual.
Sources
generic_acmg_combination_rules
BS3Not assessed: no functional study of this variant exists; the SpliceAI no-impact prediction alone is not functional evidence.
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Reasoning
BS3 requires well-established functional studies showing no damaging effect on protein function or splicing. No such study exists for this variant in any case source: there is no RNA/splicing analysis, minigene assay, or telomerase-activity assay for c.2283C>T (p.Ser761=). SpliceAI predicts no significant splice impact (max delta score 0.011) but is an in silico deep-learning prediction, not a well-established functional study, and cannot satisfy BS3 on its own; the OncoKB annotation is non-variant-specific. Absence of functional data is not evidence of benign impact, so BS3 is not_assessed rather than met.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID:25741868): BS3 = well-established functional studies show no damaging effect on protein function or splicing (strong evidence of benign impact).
Evidence considered
Governing framework: no TERT VCEP/CSPEC exists (vcep_materials.json: 'no cspec url available', final_classification_framework = generic_acmg_fallback), so generic ACMG/AMP 2015 (Richards et al., PMID:25741868) definitions apply: BS3 = well-established functional studies show no damaging effect on protein function or splicing (strong evidence of benign impact).
Screened the entire case-evidence bundle and the publications directory for functional assay data on c.2283C>T: none present — no RNA/splicing analysis, minigene assay, or telomerase-activity study exists for this exact variant in any source.
Literature pass (literature_pass.json): all 4 candidate PMIDs (20301779, 26389258, 26389333, 28492532) are gene reviews/PDQ summaries or a classification-methods paper (Sherloc), none reporting functional assays of this variant; fulltext_map.json is empty.
SpliceAI (spliceai) lookup returned near-zero delta scores (DS_AG 0.0, DS_AL 0.001, DS_DG 0.002, DS_DL 0.011; max_delta_score 0.011), predicting no significant splice impact; this is an in silico prediction from the SpliceAI deep-learning model (Jaganathan et al., Cell 2019; PMID:30661751, which recommends 0.2 as the high-confidence splice-altering cutoff), not a well-established functional study, and therefore does not satisfy BS3.
OncoKB (oncokb) 'Unknown Oncogenic Effect' annotation is non-variant-specific (is_variant_specific=false) and provides no functional assay evidence for BS3.
ClinVar Likely benign classifications (clinvar) reflect submitter curation, not functional studies, and were not used for BS3.
Still missing
No well-established functional study demonstrating absence of damaging effect on protein function or splicing for c.2283C>T; BS3 requires validated assay evidence (e.g., RNA/splicing or telomerase-activity assay with appropriate controls) for this exact variant
SpliceAI (in silico, max delta 0.011) is insufficient for BS3; a functional assay (or published RNA/telomere study) of this variant would be needed to meet it
BS4Not assessed: no affected family member tested and found not to carry the variant has been reported.
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Reasoning
No non-segregation data exist: no affected family member is reported as tested and found not to carry the variant in any source. Absence of segregation data is not evidence of non-segregation, so BS4 cannot be applied. (The variant's gnomAD frequency of ~0.02% is relevant to BA1/BS1, which are adjudicated by other groups, not to BS4.)
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID:25741868): BS4 = non-segregation with disease in affected family members (strong evidence of benign impact).
Evidence considered
Governing framework: generic ACMG/AMP 2015 (Richards et al., PMID:25741868) because no TERT VCEP/CSPEC exists (vcep_materials.json: 'no cspec url available'); BS4 = non-segregation with disease in affected family members (strong evidence of benign impact).
Searched the case-evidence bundle for non-segregation/affected-family-member testing terms: zero matches.
ClinVar record (clinvar) and all 3 submissions contain no family-testing or non-segregation assertions.
Literature pass (literature_pass.json): all 4 PMIDs have variant_mentioned=false; no non-segregation report exists for this variant; fulltext_map.json is empty.
Note: gnomAD v4.1 AF 0.00020384 (329/1,614,008 alleles, 0 homozygotes) is recorded in the case (gnomad_v4) but is population-frequency evidence for BA1/BS1/PM2 handled by other criterion groups, and was not used to infer BS4.
Still missing
No affected family members tested and found not to carry c.2283C>T
No pedigree/family testing data in any source
No publication reporting non-segregation for this variant
BP2Not assessed: no cis/trans phase information with a pathogenic variant exists.
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Reasoning
BP2 (Richards et al. 2015, PMID 25741868) requires observation of the variant in trans with a pathogenic variant for a fully dominant disease/mechanism, or in cis with a pathogenic variant. The case bundle contains no phase information at all: no trans observation with a pathogenic TERT variant in a dominant TERT phenotype, no cis observation with a pathogenic variant, and no family/segregation data. ClinVar submissions for this variant provide classifications only (three Likely benign) with no cis/trans observations, and no publication in this case reports the variant in any phased context. The criterion is therefore not assessable with the evidence available; status set to not_assessed pending phase data. The ClinVar Likely benign label is not used as phase evidence or to infer any criterion.
Rule
BP2: Observed in trans with a pathogenic variant for a fully dominant disease/mechanism; or observed in cis with a pathogenic variant (Richards et al. 2015, PMID 25741868).
Evidence considered
Generic ACMG/AMP 2015 framework (PMID 25741868) governs because no ClinGen CSPEC/VCEP specification exists for TERT; BP2 requires the variant observed in trans with a pathogenic variant for a fully dominant disease/mechanism, or in cis with a pathogenic variant.
ClinVar variation 471859 contains three Likely benign submissions with no cis/trans or phased family observations; the final classification is not used as evidence for BP2.
gnomAD v2.1, v4.1, and gnomAD-Canada population data (0 homozygotes) provide no phased proband observations and are not relevant to BP2's phase requirement.
Literature indexed for this case (PMIDs 20301779, 26389258, 26389333, 28492532) was checked via the literature pass: none reports c.2283C>T in cis or trans with a pathogenic variant; fulltext_map.json is empty (no full text available).
Still missing
No phased observation (trans or cis) of c.2283C>T with a pathogenic TERT variant exists in the case bundle.
No family or segregation data is available to establish phase for a fully dominant TERT disease/mechanism.
Confirm whether the proband's phenotype follows a fully dominant TERT mechanism, which BP2's trans arm requires.
BP5Not assessed: no proband-level molecular data exist to establish an alternate molecular basis of disease.
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Reasoning
BP5 (Richards et al. 2015, PMID:25741868) requires the variant to be found in a case with an alternate molecular basis for disease (e.g., a clearly pathogenic variant in another gene that explains the phenotype). The case bundle contains no proband-level molecular or phenotypic data that could establish an alternate molecular etiology, so BP5 cannot be evaluated and is not assessed.
Rule
generic_acmg_2015: bp5 = variant found in case with alternate molecular basis for disease (PMID:25741868); requires case-level data
Evidence considered
No proband-level molecular or phenotype data is present in the case bundle; BP5 requires evidence that the case has an alternate molecular basis for disease.
Still missing
No case-level data on an alternate molecular basis for disease (e.g., an additional clearly pathogenic variant in another gene) is present in the case bundle; BP5 cannot be evaluated without proband-level molecular and phenotype information.
Sources
generic_acmg_combination_rules
BP7Not assessed: no nucleotide conservation score is available, and the splice prediction is already counted under BP4.
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Reasoning
BP7 requires (1) a synonymous variant, (2) splicing prediction algorithms predicting no impact to the splice consensus sequence nor creation of a new splice site, AND (3) the nucleotide is not highly conserved. Conditions 1 and 2 are satisfied: the variant is synonymous (p.(Ser761=)) and SpliceAI max delta is 0.011 (no impact predicted; variant is not in a canonical +/-1,2 splice consensus position, c.2283 lying 3 nt upstream of the exon 6 donor junction). Condition 3 cannot be verified: no nucleotide conservation score (e.g., phyloP/GERP) is available anywhere in the case evidence bundle. Per group rule, evidence is therefore insufficient and the criterion is not assessed. Additionally, the same SpliceAI no-impact prediction is already applied under BP4 (supporting) per the governing framework's one-mechanism rule, so applying BP7 would double-count the same prediction; a human review is needed to obtain a conservation score and decide between BP4/BP7 application.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): BP7 = a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
SpliceAI max delta score 0.011 for NM_198253.2:c.2283C>T, below the 0.2 splice-altering cutoff from the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751); predicts no impact to the splice consensus sequence and no creation of a new splice site.
Variant is synonymous (NP_937983.2:p.(Ser761=); pvs1_variant_assessment consequence_class 'synonymous') and does not alter a canonical +/-1,2 splice consensus position (canonical_splice_consensus=false); per VariantValidator/Mutalyzer exon coordinates in prefetch.json, c.2283 is in TERT exon 6 (CDS 2131-2286), 3 nucleotides upstream of the exon 6 donor junction.
No nucleotide conservation metric (phyloP/GERP or equivalent) is present anywhere in the case evidence bundle, so the BP7 requirement that 'the nucleotide is not highly conserved' cannot be verified.
Generic ACMG/AMP 2015 BP7 definition (registry key 'generic_acmg_combination_rules', source basis Richards et al., PMID 25741868): a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site AND the nucleotide is not highly conserved.
The single available splice prediction (SpliceAI max delta 0.011) is applied exactly once in this group (BP4, supporting, per the governing operating rule); per the group rule the same prediction is not double-counted across PP3/BP4/BP7.
Still missing
Nucleotide conservation score (phyloP/GERP or equivalent) for chr5:1278759G>A (GRCh37) / chr5:1278644G>A (GRCh38) is missing from the case evidence; required to verify the 'nucleotide is not highly conserved' condition of BP7.
The splice-impact prediction (SpliceAI max delta 0.011) is already applied under BP4 (supporting) per the governing one-mechanism rule; applying BP7 on the same prediction would double-count it, so BP7 can only be applied if BP4 is relinquished for this variant.
Not applicable · 8· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: as a synonymous (silent) change, this variant triggers no null-variant mechanism such as nonsense-mediated decay.
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Reasoning
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
PS1N/ANot applicable: the variant is synonymous, so no altered amino acid exists to compare against a previously established pathogenic change.
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Reasoning
PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1N/ANot applicable: as a synonymous change, no altered residue exists to evaluate for mutational hotspot or critical-domain membership.
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Reasoning
PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM4N/ANot applicable: the synonymous change does not alter protein length, leaving nothing for this criterion to evaluate.
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Reasoning
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
PM5N/ANot applicable: no missense change exists at this residue, so there is no prior pathogenic missense to compare against.
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Reasoning
PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP2N/ANot applicable: as a synonymous change, no missense variant exists for the gene's missense-constraint properties to apply to.
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Reasoning
PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP1N/ANot applicable: as a synonymous change, this is not a missense variant in a gene with a truncating disease mechanism.
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Reasoning
BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: synonymous (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3N/ANot applicable: the variant is not an in-frame insertion/deletion in a repetitive region, so there is nothing to evaluate.
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Reasoning
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_198253.2:c.2283C>T in TERT is a synonymous (silent) substitution predicted to produce NP_937983.2:p.(Ser761=). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
AF 0.0002 · 329 / 1,614,008 alleles · 0 hom · FAF 0.00025
European (non-Finnish)324 / 1,180,054
0.00027
Remaining individuals3 / 62,488
4.8e-05
African/African American2 / 74,948
2.7e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 2.8e-05 · 7 / 251,342 alleles · 0 hom · FAF 2.9e-05
European (non-Finnish)7 / 113,638
6.2e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00020384; MAF= 0.02038%, 329/1614008 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000274564; MAF= 0.02746%, 324/1180054 alleles, homozygotes = 0); grpmax FAF= 0.00024924.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.78505e-05; MAF= 0.00279%, 7/251342 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.15991e-05; MAF= 0.00616%, 7/113638 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
BP4SupportingMet (Supporting): SpliceAI max delta 0.011 is below the 0.1 threshold, predicting no impact on splicing for this synonymous variant.
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Reasoning
Governing generic ACMG/AMP framework (registry key 'generic_acmg_combination_rules'; Richards et al. 2015, PMID 25741868) pre-assigns BP4 (supporting) for synonymous/non-missense variants whose SpliceAI max delta is < 0.1 (SVI-recommended thresholds codified in the framework document). SpliceAI max delta for c.2283C>T is 0.011 (< 0.1), predicting no impact on splicing, so BP4 is met at supporting strength. This is the single splice-path prediction applied for this variant per the framework's one-mechanism rule; it is not double-counted into BP7. Missense predictors are not applicable (synonymous variant) and BayesDel is not usable (no verified published threshold).
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868) with lab operating thresholds for non-VCEP cases: BP4 = computational evidence suggests no impact on gene/gene product; for synonymous/non-missense variants use SpliceAI only, max delta < 0.1 -> BP4 (supporting).
Evidence considered
SpliceAI max delta score 0.011 (DS_AG=0.000, DS_AL=0.001, DS_DG=0.002, DS_DL=0.011) is below the 0.1 threshold at which the governing generic framework assigns BP4 (supporting) for synonymous/non-missense variants, and far below the 0.2 splice-altering cutoff from the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751).
Governing framework (registry key 'generic_acmg_combination_rules', source basis Richards et al. 2015, PMID 25741868) operating rule for non-VCEP cases: for intronic/synonymous/non-canonical-splice-position variants use SpliceAI only; SpliceAI max delta < 0.1 -> BP4 (supporting); max delta 0.1-0.2 gray zone (neither met).
REVEL score not found and BayesDel score not found in case data; aGVGD not present. Per the framework's one-mechanism rule, only the splice path is evaluated for this synonymous variant, so the absent missense predictors do not block the BP4 call.
PP3Not met: SpliceAI max delta 0.011 is far below the 0.2 splice-altering cutoff, and no missense predictors apply to this synonymous change.
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Reasoning
No computational evidence supports a deleterious effect. SpliceAI (registry key 'spliceai') reports max delta score 0.011 for NM_198253.2:c.2283C>T (DS_AG=0.000, DS_AL=0.001, DS_DG=0.002, DS_DL=0.011), far below the 0.2 splice-altering cutoff from the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751), so no splice impact and no de novo splice site is predicted. The variant is synonymous (NP_937983.2:p.(Ser761=)), so the missense in-silico path (REVEL/BayesDel/aGVGD) is not applicable; REVEL returned no score and BayesDel returned no score in this case, and BayesDel has no verified published threshold under the governing rule. The governing generic ACMG framework's operating threshold for PP3 (SpliceAI max delta > 0.2, for non-missense variants) is not approached.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868) with lab operating thresholds for non-VCEP cases: PP3 = computational evidence supports a deleterious effect; for synonymous/non-missense variants use SpliceAI only, max delta > 0.2 -> PP3 (supporting); BayesDel never used (no verified threshold).
Evidence considered
SpliceAI lookup (registry key 'spliceai') returns max delta score 0.011 for NM_198253.2:c.2283C>T (DS_AG=0.000, DS_AL=0.001, DS_DG=0.002, DS_DL=0.011), far below the 0.2 splice-altering cutoff recommended in the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751); no significant splice impact and no creation of a new splice site predicted.
Governing framework: no ClinGen CSPEC/VCEP specification exists for TERT (vcep_materials: 'no cspec url available', gene_vcep_dir null; case framework_mode 'generic_acmg'), so generic ACMG/AMP 2015 (Richards et al., PMID 25741868; registry key 'generic_acmg_combination_rules') applies. Its operating in-silico rule for synonymous/non-missense variants uses SpliceAI only, with SVI-recommended thresholds (as codified in the framework document, attributed there to Walker et al. 2023): max delta > 0.2 -> PP3 (supporting), max delta < 0.1 -> BP4 (supporting), 0.1-0.2 gray zone; BayesDel is explicitly excluded because no verified published threshold is available.
Variant is synonymous (NP_937983.2:p.(Ser761=); pvs1_variant_assessment consequence_class 'synonymous', canonical_splice_consensus=false). Per VariantValidator/Mutalyzer exon coordinates in prefetch.json, c.2283 lies in TERT exon 6 (CDS 2131-2286), 3 nucleotides upstream of the exon 6 donor junction, i.e., a non-canonical exonic splice-region position.
REVEL lookup returned no score (evidence.json revel.found=false) and BayesDel lookup returned no score (evidence.json bayesdel.found=false); aGVGD is not present in this case. REVEL and other missense predictors are not applicable to a synonymous substitution, and BayesDel is not usable under the governing rule.
Still missing
No damaging prediction from any computational tool; missense-path predictors (REVEL/BayesDel/aGVGD) are absent in this case, though they are not applicable to a synonymous variant and their absence does not change the PP3 outcome.
BP7Not assessed: no nucleotide conservation score is available, and the splice prediction is already counted under BP4.
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Reasoning
BP7 requires (1) a synonymous variant, (2) splicing prediction algorithms predicting no impact to the splice consensus sequence nor creation of a new splice site, AND (3) the nucleotide is not highly conserved. Conditions 1 and 2 are satisfied: the variant is synonymous (p.(Ser761=)) and SpliceAI max delta is 0.011 (no impact predicted; variant is not in a canonical +/-1,2 splice consensus position, c.2283 lying 3 nt upstream of the exon 6 donor junction). Condition 3 cannot be verified: no nucleotide conservation score (e.g., phyloP/GERP) is available anywhere in the case evidence bundle. Per group rule, evidence is therefore insufficient and the criterion is not assessed. Additionally, the same SpliceAI no-impact prediction is already applied under BP4 (supporting) per the governing framework's one-mechanism rule, so applying BP7 would double-count the same prediction; a human review is needed to obtain a conservation score and decide between BP4/BP7 application.
Rule
Generic ACMG/AMP 2015 (Richards et al., PMID 25741868): BP7 = a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site AND the nucleotide is not highly conserved.
Evidence considered
SpliceAI max delta score 0.011 for NM_198253.2:c.2283C>T, below the 0.2 splice-altering cutoff from the SpliceAI publication (Jaganathan et al. 2019, PMID 30661751); predicts no impact to the splice consensus sequence and no creation of a new splice site.
Variant is synonymous (NP_937983.2:p.(Ser761=); pvs1_variant_assessment consequence_class 'synonymous') and does not alter a canonical +/-1,2 splice consensus position (canonical_splice_consensus=false); per VariantValidator/Mutalyzer exon coordinates in prefetch.json, c.2283 is in TERT exon 6 (CDS 2131-2286), 3 nucleotides upstream of the exon 6 donor junction.
No nucleotide conservation metric (phyloP/GERP or equivalent) is present anywhere in the case evidence bundle, so the BP7 requirement that 'the nucleotide is not highly conserved' cannot be verified.
Generic ACMG/AMP 2015 BP7 definition (registry key 'generic_acmg_combination_rules', source basis Richards et al., PMID 25741868): a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor creation of a new splice site AND the nucleotide is not highly conserved.
The single available splice prediction (SpliceAI max delta 0.011) is applied exactly once in this group (BP4, supporting, per the governing operating rule); per the group rule the same prediction is not double-counted across PP3/BP4/BP7.
Still missing
Nucleotide conservation score (phyloP/GERP or equivalent) for chr5:1278759G>A (GRCh37) / chr5:1278644G>A (GRCh38) is missing from the case evidence; required to verify the 'nucleotide is not highly conserved' condition of BP7.
The splice-impact prediction (SpliceAI max delta 0.011) is already applied under BP4 (supporting) per the governing one-mechanism rule; applying BP7 on the same prediction would double-count it, so BP7 can only be applied if BP4 is relinquished for this variant.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
4 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
Dyskeratosis Congenita and Related Telomere Biology Disorders.
Adam MP et al. · 1993
GeneReviews chapter on Dyskeratosis Congenita and Related Telomere Biology Disorders, retrieved via the ClinVar prefetch and triaged as a candidate PS4/PP5 reference. The available record contains no abstract or full-text content in the case bundle, no case-control prevalence data, and no mention of TERT c.2283C>T (p.Ser761=); it does not support PS4 or PP5 for this variant.
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
PDQ Cancer Genetics Editorial Board · 2002
PDQ Cancer Genetics Risk Assessment and Counseling (Health Professional Version), retrieved via the ClinVar prefetch and triaged as a candidate PS4/PP5 reference. The available record contains no abstract or full-text content in the case bundle, no case-control data, and no mention of TERT c.2283C>T; it does not support PS4 or PP5 for this variant.
Genetics of Skin Cancer (PDQ®): Health Professional Version.
PDQ Cancer Genetics Editorial Board · 2002
PDQ Genetics of Skin Cancer (Health Professional Version), retrieved via the ClinVar prefetch and triaged as a candidate PS4/PP5 reference. The available record contains no abstract or full-text content in the case bundle, no case-control data, and no mention of TERT c.2283C>T; it does not support PS4 or PP5 for this variant.
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
Nykamp K et al. · 2017
Sherloc (Nykamp et al., Genet Med 2017), a methodology paper refining ACMG-AMP criteria weighting; retrieved as the validated PMID cited by the Labcorp/Invitae ClinVar submission (SCV000650740). It is background/methodology content with no data on TERT c.2283C>T and does not support any criterion in this group.
The 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines were a major step toward establishing a common framework for variant classification.
Abstract (publications.json record for PMID:28492532).
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1329 / 1,614,008 recorded allelesOpen source ↗
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00020384; MAF= 0.02038%, 329/1614008 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000274564; MAF= 0.02746%, 324/1180054 alleles, homozygotes = 0); grpmax FAF= 0.00024924.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.78505e-05; MAF= 0.00279%, 7/251342 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.15991e-05; MAF= 0.00616%, 7/113638 alleles, homozygotes = 0); grpmax FAF= 2.856e-05.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories). (ClinVarID = 471859)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57215940, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
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