No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.MYCL encodes a transcription factor of the MYC oncoprotein family that regulates gene expression via RNA polymerase II-mediated transcription. Unlike the ubiquitously expressed MYC, MYCL is preferentially expressed in the developing kidney and lung. MYCL functions as an oncogene, with amplification found in approximately 5-10% of small cell lung carcinomas, sometimes co-occurring with amplification of other MYC family members.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (moderate): gnomAD v2.1 AF 3.98e-06 and v4.1 AF 2.48e-06, both far below the <0.1% threshold, with zero homozygotes.
Met (supporting): REVEL 0.914 and BayesDel 0.499 both predict a deleterious missense effect.
No benign criterion marked as applied in the recorded assessment.
VUS: only PM2 (moderate) and PP3 (supporting) are met, and that combination satisfies no pathogenic or benign rule under the generic ACMG/AMP 2015 framework.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 4 / 1,614,198 alleles. Recorded AF 2.47801e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 3.97624e-06; MAF= 0.00040%, 1/251494 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78982e-06; MAF= 0.00088%, 1/113768 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYCL, a transcription factor, is altered by overexpression and amplification in various cancer types including small cell lung cancer.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No ClinGen CSPEC/VCEP specification exists for MYCL (vcep_materials.json framework_complete=false); generic ACMG/AMP 2015 (Richards et al., PMID 25741868) is the governing framework (generic_acmg_combination_rules).
PS1 not met: the only ClinVar record (VCV003297294) is the case variant itself (VUS, single submitter, no PMIDs, no expert panel); no established pathogenic variant producing p.Arg321Gly from a different nucleotide change was identified.
PM1 not met: CANCERHOTSPOTS returned no significant hotspot for MYCL R321; OncoKB has no variant-specific functional evidence; no critical functional domain definition was retrieved, and MYCL's mechanism is amplification/overexpression rather than missense.
PM5 not assessed: pm5_candidates.json could not confirm classic same-residue PM5 semantics (pm5_mode=unknown) and collected zero comparator candidates; no literature (0 PMIDs). Manual ClinVar/literature search for pathogenic alternate missense at p.Arg321 is required (needs_human_review=true).
PP2 not met: no evidence that MYCL has a low rate of benign missense variation (constraint metric not captured) or that missense is a common mechanism of disease (gene context/OncoKB describe amplification/overexpression).
BP1 not met: MYCL is not a gene for which only truncating variants cause disease; its oncogenic mechanism is activation (amplification/overexpression).
Net contribution of this group: no positive (PS1/PM1/PM5/PP2) and no negative (BP1) criteria are met; the group provides no evidence toward the final classification on the current evidence base.
No ClinGen CSPEC/VCEP specification exists for MYCL (cspec.found=false, gene_vcep_dir=null, final_classification_framework.found=false), so the generic ACMG/AMP 2015 framework (PMID:25741868, generic_acmg_combination_rules) governs this case.
The case bundle contains no proband phenotype, no parental-testing results, and no family/pedigree segregation data for NM_001033082.2:c.961C>G (MYCL p.Arg321Gly); all segregation/de novo criteria (PS2, PM6, PP1, BS4) are therefore not_assessed with the specific missing evidence identified as gaps.
ClinVar VCV003297294 is a 1-star single-submitter (Ambry Genetics) germline VUS with condition 'not specified' and no criteria, de novo, or segregation annotations; literature_pass identified 0 PMIDs and fulltext_map is empty, so no publication could be reviewed for this group.
MYCL is a proto-oncogene (L-Myc) with no established germline Mendelian disease association in this case's evidence set; population (gnomAD v2.1 AF 3.98e-06, v4.1 AF 2.48e-06, no homozygotes; gnomAD-Canada absent) and functional (SpliceAI max delta 0.01, REVEL 0.914, OncoKB unknown effect, COSMIC absent) sources carry no segregation-relevant information.
If proband-parent trio testing or family segregation data are later provided, PS2/PM6/PP1/BS4 must be re-adjudicated with those data.
Functional group contributes no evidence to the final classification: both PS3 (deleterious functional effect) and BS3 (benign functional effect) are not_assessed because no well-established functional study data exist for MYCL c.961C>G (p.Arg321Gly). Absence of functional evidence is a neutral gap and does not support either pathogenicity or benignity.
Governing framework: no ClinGen CSPEC or VCEP specification exists for MYCL (cspec found=false, final_classification_framework.source=generic_acmg_fallback, precedence_rank 3), so generic ACMG/AMP 2015 (PMID:25741868) via generic_acmg_combination_rules governs PS3/BS3, requiring well-established functional studies with validated assays and controls.
Only sources directly consulted for PS3/BS3 were used (oncokb, clinvar, spliceai, revel, bayesdel, generic_acmg_combination_rules); in-silico predictions were explicitly excluded as functional evidence. No other source's final classification was inferred.
No MYCL CSPEC/VCEP exists for this case (vcep_materials.json: 'no cspec url available'; cspec.found=false; gene_vcep_dir=null; final_classification_framework=generic_acmg_fallback, precedence_rank=3); generic ACMG/AMP 2015 (PMID:25741868, source_registry key generic_acmg_combination_rules) governs PS4/PP4/PP5/BP5/BP6.
PS4 is not_assessed: no case-control or cohort enrichment data exist for the exact variant. literature_pass total_pmids=0, ClinVar VCV003297294 has validated_pmids=0 and its single submission provides no case counts or controls; gnomAD v2.1/v4.1 show ultra-rare population frequencies (0 homozygotes), the opposite of an enrichment signal.
PP4 is not_assessed: no proband phenotype or family history is present in any case source; the sole ClinVar submission lists condition 'not specified', and no publication reports any carrier phenotype.
PP5 is not_met: ClinVar VCV003297294 has zero expert-panel submissions (expert_panel_submissions=0, review_stars=1, single ordinary laboratory VUS); the aggregate 'Uncertain significance' label cannot trigger PP5 under the expert-panel-only rule.
BP5 is not_assessed: no proband-level data on an alternative molecular cause (no other-gene findings, no proband phenotype, no case narratives).
BP6 is not_met: no Benign/Likely benign submission exists for this exact variant, and there is no expert-panel benign assertion; BP6 cannot be triggered.
No criterion was inferred from another source's final classification: the ClinVar 'Uncertain significance' label was used only to document the absence of expert-panel assertions and of case/phenotype data.
This group contributes no met criteria; it yields no pathogenic or benign points toward the final classification pending case-control, proband-phenotype, and alternate-diagnosis data.
PM3 not_assessed: no phase data, no pathogenic variant in trans, no affected-proband observations, and no established autosomal-recessive germline disease association for MYCL (proto-oncogene).
BP2 not_assessed: no pathogenic variant identified in cis or trans with c.961C>G, no phase/pedigree data, and no established dominant germline disease association for MYCL.
Framework: generic ACMG/AMP 2015 fallback applied because no CSPEC/VCEP specification exists for MYCL (generic_acmg_combination_rules, PMID:25741868).
Governing framework: no ClinGen CSPEC/VCEP specification exists for MYCL (cspec found=false; vcep_materials empty), so PP3/BP4 are adjudicated under the generic ACMG/AMP 2015 fallback (Richards et al., PMID 25741868) via generic_acmg_combination_rules.
PP3 met (supporting): REVEL 0.914 and BayesDel (noAF) 0.499098 provide two independent missense in-silico lines predicting a deleterious effect. Strength kept at the generic supporting default; calibrated strong thresholds are exceeded but no MYCL VCEP rule exists to formalize an upgrade.
BP4 not met: both missense in-silico tools predict pathogenicity (REVEL 0.914, BayesDel 0.499098), contradicting BP4. SpliceAI (max delta 0.01) predicts no splice impact but is a single tool and does not address missense effect; it cannot satisfy BP4's multiple-lines requirement on its own.
No variant-specific publications were available for this group: literature_pass.json reports 0 PMIDs across all evidence sources and fulltext_map.json is empty; no papers were reviewed for PP3/BP4.
BP7 (synonymous) is out of scope: the variant is a missense change (p.Arg321Gly), not synonymous.
Framework: no ClinGen CSPEC, no VCEP, and no local custom gene framework exists for MYCL; generic ACMG/AMP 2015 fallback applied (final_classification_framework.json: found=false, framework_complete=false, precedence_rank=3, scoring_model=ACMG/AMP 2015).
Gene context: MYCL is a proto-oncogene (bHLH transcription factor) altered by overexpression/amplification in small cell lung cancer; it has no established monogenic germline disorder, so disease prevalence- and penetrance-based calibrations are unavailable.
Population data (variant NM_001033082.2:c.961C>G, p.(Arg321Gly)): gnomAD v2.1 total AF 3.98e-06 (0.00040%, 1/251,494), gnomAD v4.1 total AF 2.48e-06 (0.00025%, 4/1,614,198), 0 homozygotes in both, grpmax FAF 7.9e-07 (v4.1), absent from gnomAD-Canada v1.0; highest subpopulation AF 0.00088% (NFE, v2.1).
BA1 not met: AF is 3-4 orders of magnitude below the BA1 threshold (>1%/>5%).
BS1 not met: AF is ~750-1200x below the 0.3% non-VCEP threshold and below any plausible disease-allele expectation; no disease model exists to calibrate otherwise.
BS2 not applicable: no established MYCL monogenic disorder/penetrance model, and population data show 0 homozygotes with only 1-4 heterozygous alleles - no healthy-adult enrichment evidence.
PM2 met (Moderate, generic ACMG/AMP 2015): all population frequencies are far below the <0.1% threshold with 0 homozygotes; SVI-style PM2_Supporting strength caveat recorded for downstream combination.
No criteria match.
PM2 (Richards et al. 2015) is met: the variant is absent or at extremely low frequency in population databases. gnomAD v2.1 total AF = 3.976e-06 (0.00040%, 1/251,494 alleles, 0 homozygotes; max subpop NFE AF 0.00088%); gnomAD v4.1 total AF = 2.478e-06 (0.00025%, 4/1,614,198 alleles, 0 homozygotes; max subpop NFE AF 0.00034%; grpmax FAF 7.9e-07); variant absent from gnomAD-Canada v1.0. All observed frequencies are well below the non-VCEP PM2 threshold (<0.1%), with no homozygotes in any ancestry group. Under the generic ACMG/AMP 2015 fallback, PM2 is applied at Moderate strength; note that ClinGen SVI-calibrated frameworks frequently apply PM2 at supporting strength (PM2_Supporting) - this strength caveat is recorded for downstream combination, but the criterion itself is met.
generic_acmg: PM2 requires absent or extremely low AF in population databases; non-VCEP fallback threshold PM2 < 0.1%
Two independent missense in-silico tools both predict a deleterious effect. REVEL = 0.914 (local REVEL v1.3 lookup, chr1:39897596 G>C), far above standard pathogenic thresholds (0.5 supporting / 0.75 strong). BayesDel (noAF) = 0.499098, also above standard pathogenic thresholds. These constitute multiple lines of computational evidence supporting a deleterious effect on the gene product, meeting generic PP3. SpliceAI (max delta 0.01) predicts no splice impact, which does not contradict PP3 for a missense variant. Strength is set to supporting per the generic ACMG/AMP 2015 default (PMID 25741868) because MYCL has no VCEP/CSPEC specification; note that both tools individually exceed strong calibrated thresholds (e.g. Pejaver et al. 2022-style calibration), so PP3 could be upgraded if a MYCL-specific rule later formalizes calibration - this does not double-count, as it remains the same single criterion.
PP3 (Richards et al. 2015, PMID 25741868): multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.); supporting strength under generic ACMG/AMP.
PS1 requires the identical amino acid change (p.Arg321Gly) produced by a DIFFERENT nucleotide change to be previously established as pathogenic. The only ClinVar record for this locus (VCV003297294) is the case variant itself, listed under the alternate MYCL transcript as NM_001033081.3:c.871C>G (p.Arg291Gly) — the same genomic change (NC_000001.10:g.40363268G>C), not a different-nucleotide variant. That record is classified Uncertain significance by a single clinical laboratory (Ambry Genetics, SCV005139027, criteria provided/single submitter, 1 star) with no PMIDs, no expert panel, and no criterion leads. The pm5_candidates artifact collected zero comparator candidates and literature_pass.json reports 0 PMIDs, so no established pathogenic variant producing p.Arg321Gly via an alternate nucleotide change was identified. PS1 therefore cannot be met on the available evidence. Gap: a curated ClinVar/literature search for alternate-nucleotide variants that also encode p.Arg321Gly (e.g., c.961C>A) was not executed by the pipeline, so absence is based on the collected records only.
PS1 (Richards et al. 2015, PMID 25741868): same amino acid change as a previously established pathogenic variant regardless of nucleotide change
PM1 requires the variant to be located in a mutational hotspot and/or a critical and well-established functional domain without benign variation. Direct queries found no hotspot: CANCERHOTSPOTS search 'MYCL R321' returned no_result (evidence.json hotspots), and OncoKB (MYCL/R321G) reports no variant-specific reviewed functional evidence, classifying the variant 'Unknown Oncogenic Effect' (not_reviewed=true). No ClinGen CSPEC/VCEP defines a critical functional domain for MYCL (vcep_materials.json framework_complete=false), and no domain-coordinate annotation (e.g., UniProt/Pfam bHLH boundaries) was retrieved in gene_context_MYCL.json. Gene-level context and OncoKB describe MYCL's oncogenic mechanism as amplification/overexpression (e.g., ~5-10% of small cell lung carcinomas), not recurrent germline/somatic missense activation, so the missense-mechanism premise of PM1 is unsupported. PM1 is therefore not met on the available evidence.
PM1 (Richards et al. 2015, PMID 25741868): located in a mutational hotspot and/or critical and well-established functional domain without benign variation
PP2 requires BOTH (a) a low rate of benign missense variation in the gene (missense constraint) AND (b) missense as a common mechanism of disease. No gnomAD missense constraint metric (missense Z-score/pLI) for MYCL was captured in the bundle, so condition (a) is unevaluated. For condition (b), the available evidence points against missense as the disease mechanism: gene_context_MYCL.json and OncoKB describe MYCL as a proto-oncogene activated by amplification/overexpression in cancers (e.g., small cell lung cancer), and there is no VCEP/CSPEC guidance establishing a germline missense mechanism (vcep_materials.json framework_complete=false). MYCL (OMIM 164850) has no established germline Mendelian disease phenotype in the collected evidence. With no support for the missense-mechanism condition and no constraint data for the low-benign-missense condition, PP2 is not met on the available evidence.
PP2 (Richards et al. 2015, PMID 25741868): missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Per this group's governing rule, PP5 is triggered ONLY by an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic. ClinVar VCV003297294 has expert_panel_submissions=0: the single submission (SCV005139027, Ambry Genetics, clinical testing, germline) is flagged is_expert_panel=false, has review status 'criteria provided, single submitter' (1 star, not a 3-star expert panel), and is classified 'Uncertain significance'. The aggregate label is therefore an ordinary laboratory VUS assertion, which must never trigger PP5. No reputable-source expert-panel pathogenic/likely-pathogenic assertion exists for this exact variant (no PMIDs, no criterion leads, no panel submissions), so PP5 is not met.
Group PP5 rule (expert-panel-only, per pp5-bp6-rule-engine-gap): PP5 triggered ONLY by an exact-variant ClinVar expert-panel (3-star) Pathogenic/Likely pathogenic classification; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger PP5.
BA1 (Richards et al. 2015, PMID:25741868) requires an allele frequency >5% (0.05) in a large, ethnically diverse population dataset (pipeline non-VCEP threshold for this fallback: BA1 >1%). The observed frequencies are orders of magnitude below any BA1 threshold: gnomAD v2.1 total AF = 3.976e-06 (0.00040%, 1/251,494 alleles, 0 homozygotes) with highest subpopulation AF = 8.79e-06 (0.00088%, NFE); gnomAD v4.1 total AF = 2.478e-06 (0.00025%, 4/1,614,198 alleles, 0 homozygotes) with highest subpopulation AF = 3.39e-06 (0.00034%, NFE) and grpmax FAF = 7.9e-07. The variant is also absent from gnomAD-Canada v1.0. There is no evidence of a common, benign polymorphism; BA1 is not met.
generic_acmg: BA1 requires AF > 0.05 (5%) in a large, ethnically diverse cohort; non-VCEP fallback threshold BA1 > 1%
BS1 (Richards et al. 2015) requires an allele frequency greater than expected for the disorder. MYCL has no established monogenic germline disorder (gene context: somatic proto-oncogene amplified in small cell lung cancer), so no disease-allele frequency expectation can be formally calibrated; evaluated against the pipeline non-VCEP fallback threshold of BS1 >0.3%. Observed frequencies (gnomAD v2.1 total AF 0.00040%, max subpop 0.00088%; gnomAD v4.1 total AF 0.00025%, max subpop 0.00034%) are roughly 750-1200x below the 0.3% threshold and far below any plausible disease-allele expectation. BS1 is not met.
generic_acmg: BS1 requires AF greater than expected for the disorder; non-VCEP fallback threshold BS1 > 0.3%
BP1 applies when a missense variant occurs in a gene for which primarily truncating (loss-of-function) variants are known to cause disease. MYCL is not such a gene: it is a proto-oncogene whose cancer-relevant mechanism is activation via amplification and overexpression (gene_context_MYCL.json; OncoKB gene-level curation), the opposite of a truncation/LOF-only disease gene. No VCEP/CSPEC or literature in this case indicates that only truncating variants cause MYCL-related disease. BP1 therefore cannot be applied.
BP1 (Richards et al. 2015, PMID 25741868): missense variant in a gene for which primarily truncating variants are known to cause disease
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. The missense in-silico lines point in the opposite direction: REVEL 0.914 and BayesDel 0.499098 both predict a deleterious effect, directly contradicting a no-impact conclusion. The only potentially BP4-consistent line is SpliceAI (max delta 0.01, all four delta scores <= 0.01), which predicts no splice impact; however, a single splice predictor without concordant benign missense predictions does not satisfy the 'multiple lines' requirement of generic BP4, and the splice result does not address missense pathogenicity. BP4 is therefore not met.
BP4 (Richards et al. 2015, PMID 25741868): multiple lines of computational evidence suggest no impact on the gene or gene product; supporting strength under generic ACMG/AMP.
Per this group's governing rule, BP6 is triggered ONLY by an exact-variant ClinVar expert-panel classification of Benign/Likely benign. ClinVar VCV003297294 contains no Benign or Likely benign submission whatsoever: the single submission (SCV005139027, Ambry Genetics) is 'Uncertain significance', expert_panel_submissions=0, review_stars=1, and is_expert_panel=false. There is no reputable-source expert-panel benign assertion for this exact variant, so BP6 is not met.
Group BP6 rule (expert-panel-only, per pp5-bp6-rule-engine-gap): BP6 triggered ONLY by an exact-variant ClinVar expert-panel (3-star) Benign/Likely benign classification; ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions never trigger BP6.
PS2 (Richards et al. 2015, PMID:25741868) requires a documented de novo occurrence of the variant in a proband whose biological parents have been tested and confirmed (parentage verified), with the variant absent in both parents and the proband phenotype consistent with the gene's disease. The case bundle (review_manifest, case_summary, prefetch, evidence, literature_pass, vcep_materials, fulltext_map) contains no proband clinical data, no phenotype description, and no parental-testing/trio results for NM_001033082.2:c.961C>G (MYCL p.Arg321Gly). ClinVar (VCV003297294) is a 1-star single-submitter germline VUS with condition 'not specified', no criteria provided, and no de novo or parental-testing annotation. No publication in the case (literature_pass total_pmids=0; fulltext_map empty) reports the variant in a proband-parent trio. Without any de novo observation, PS2 cannot be evaluated. Governing framework: generic ACMG/AMP 2015 fallback (no MYCL CSPEC/VCEP exists; framework_complete=false).
generic ACMG/AMP 2015 (PMID:25741868) PS2 - requires confirmed de novo variant with verified parentage in a phenotypically consistent proband; not assessable without proband-parent trio data
PS3 requires well-established functional studies demonstrating a deleterious effect, applied at strong strength only when a validated assay with appropriate controls and demonstrated biological relevance exists (generic ACMG/AMP 2015, PMID:25741868, per generic_acmg_combination_rules). No functional assay evidence exists for MYCL c.961C>G (p.Arg321Gly): the literature pass returned 0 PMIDs (literature_pass.json total_pmids=0), the publications directory and fulltext_map.json are empty, and no VCEP/CSPEC specification for MYCL is available to calibrate assay requirements. OncoKB explicitly states it 'did not identify variant-specific reviewed functional evidence for this variant' (classification: Unknown Oncogenic Effect, not_reviewed=true, is_variant_specific=false). The single ClinVar submission (VCV003297294, Ambry Genetics, Uncertain significance, SCV005139027) provides no criteria, no PMIDs, and no functional data. COSMIC absence and CancerHotspots non-membership are absence-of-occurrence observations in somatic cancer datasets, not functional assay results, and neither source is a key in the source registry. In-silico predictors (REVEL 0.914, BayesDel 0.499, SpliceAI max delta 0.01) are computational predictions and are explicitly excluded from PS3/BS3, which require wet-lab functional assays with controls. Evidence is therefore insufficient to apply PS3: no functional study exists in either direction, so the criterion is not_assessed rather than affirmatively not_met.
PS3 (generic ACMG/AMP 2015, PMID:25741868 via generic_acmg_combination_rules): Well-established functional studies showing a deleterious effect; strong strength, requires a validated assay with controls and biological relevance. Not applicable in the absence of functional study evidence.
Generic ACMG/AMP 2015 (PMID:25741868) governs this case (no MYCL CSPEC/VCEP: cspec.found=false, gene_vcep_dir=null, framework_mode=generic_acmg; see generic_acmg_combination_rules). PS4 requires the prevalence of the variant in affected individuals to be significantly increased compared with controls (case-control/cohort enrichment with statistical support). No case-control or cohort study of the exact variant exists anywhere in the bundle: literature_pass.json reports total_pmids=0, ClinVar VCV003297294 has zero validated PMIDs (validated_pmids=0, criterion_lead_submissions=0), and fulltext_map.json is empty. The only ClinVar submission (SCV005139027, Ambry Genetics, 'Uncertain significance', clinical testing) provides no case counts, no controls, and no enrichment statistic. Population data show the opposite of an enrichment signal: gnomAD v2.1 AF=3.98e-06 (1/251,494 alleles, 0 homozygotes) and gnomAD v4.1 AF=2.48e-06 (4/1,614,198 alleles, 0 homozygotes). Returned not_assessed rather than not_met because the decisive evidence class (variant-genotyped cases vs. controls with statistics) is absent, not refuted.
Generic ACMG/AMP 2015 (PMID:25741868) PS4: 'The prevalence of the variant in affected individuals is significantly increased compared with controls.' Requires case-control/cohort enrichment with statistical support; variant observation without control comparison is insufficient.
Generic ACMG/AMP 2015 PM3 ('for recessive disorders, detected in trans with a pathogenic variant') cannot be evaluated because the evidence bundle contains no allele-phase or segregation data for MYCL (NM_001033082.2:c.961C>G, p.Arg321Gly). No pathogenic variant in MYCL is identified anywhere in the case: ClinVar (variation 3297294) is a single-submitter Uncertain significance entry (Ambry Genetics, SCV005139027) with no criteria provided, no PMIDs, and condition 'not specified'; the literature pass returned 0 PMIDs (fulltext_map is empty); gnomAD v2.1/v4.1 and gnomAD-Canada provide only population allele frequencies (v4.1 AF 2.48e-06, 0 homozygotes) with no family observations. There are therefore no affected-proband observations, no second-allele variant, and no phase determination (cis/trans) to support PM3. In addition, MYCL is a proto-oncogene (bHLH transcription factor) with no established autosomal-recessive germline disease association (pvs1_gene_context reports inheritance: [] and germline context as literature_only), so the precondition that the gene causes an autosomal recessive disorder is itself unverified. Per the group instruction, insufficient evidence is recorded as not_assessed with the gap identified.
Generic ACMG/AMP 2015 (PMID:25741868) PM3: for recessive disorders, variant detected in trans with a pathogenic variant. No VCEP/CSPEC specification exists for MYCL (cspec found: false; framework_mode: generic_acmg; source: generic_acmg_combination_rules).
PM5 requires a novel missense change at an amino acid residue where a DIFFERENT missense change has previously been established as pathogenic. The pm5_candidates artifact could not confirm classic same-residue PM5 semantics for MYCL (pm5_mode=unknown; eligible_for_classic_pm5_search=false) and skipped automatic candidate harvesting; zero comparator candidates were collected, and its recommendation explicitly states PM5 should not be applied from the artifact alone. ClinVar contains no alternate missense variants at Arg321 (the only record is the case variant itself, VUS), and literature_pass.json reports 0 PMIDs with no publications available. There is therefore no evidence base to determine whether PM5 is met. A manual ClinVar/literature search for pathogenic alternate missense changes at p.Arg321 (e.g., p.Arg321His, p.Arg321Cys, p.Arg321Ser, p.Arg321Leu) is required before PM5 can be adjudicated; flagged for human review.
PM5 (Richards et al. 2015, PMID 25741868): novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
PM6 (Richards et al. 2015, PMID:25741868) requires an assumed de novo occurrence of the variant in a proband when parental samples have not been tested or parentage is unconfirmed, with phenotype consistency. The case bundle contains no proband-level observation of NM_001033082.2:c.961C>G arising de novo, no proband phenotype, and no statement that parental samples were untested. ClinVar VCV003297294 (germline VUS, 1-star, condition 'not specified') carries no de novo annotation, and no literature exists in this case (0 PMIDs). PM6 is therefore not assessable. Governing framework: generic ACMG/AMP 2015 fallback (no MYCL CSPEC/VCEP exists).
generic ACMG/AMP 2015 (PMID:25741868) PM6 - requires assumed de novo variant (parental testing not performed or unconfirmed) in a phenotypically consistent proband; not assessable without proband de novo observation
PP1 (Richards et al. 2015, PMID:25741868) is a supporting criterion for co-segregation of the variant with disease in multiple affected family members (number of informative meioses determines strength per ACMG/AMP: e.g., >=2 meioses supporting). The case bundle contains no pedigree, no affected family members tested for NM_001033082.2:c.961C>G, and no segregation or meioses data. ClinVar VCV003297294 reports a single germline VUS submission with no family/segregation annotation, and no relevant publications exist (0 PMIDs). Without any segregation observations, PP1 cannot be evaluated (neither met nor contradicted). Governing framework: generic ACMG/AMP 2015 fallback (no MYCL CSPEC/VCEP exists).
generic ACMG/AMP 2015 (PMID:25741868) PP1 - requires co-segregation of variant with disease in affected family members (meioses count); not assessable without family segregation data
Generic ACMG/AMP 2015 (PMID:25741868) PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology, anchored to the proband under interpretation. The case bundle contains no proband clinical data of any kind: case_summary.json has no phenotype, family history, or segregation fields; the sole ClinVar submission (SCV005139027, Ambry Genetics) has an empty conditions list with record-level api_conditions ['not specified']; and no publication exists for this variant (literature_pass total_pmids=0). No carrier phenotype can be inferred from any source. Additionally, MYCL has no established highly-specific single-etiology germline phenotype in this bundle (the gene-context literature in pvs1_gene_context.json is germline-disease-context material for the PVS1 group only and does not mention this variant). Returned not_assessed rather than not_met because the proband phenotype data class is missing entirely.
Generic ACMG/AMP 2015 (PMID:25741868) PP4: 'Phenotype or family history highly specific for a disease with a single genetic etiology.' Requires proband-level phenotype/family-history specificity; no such data exist in this case.
BS3 requires well-established functional studies demonstrating no damaging effect, applied at strong strength only for validated assays with appropriate controls (generic ACMG/AMP 2015, PMID:25741868, per generic_acmg_combination_rules). No functional evidence of any kind is available for this variant: literature_pass.json returned 0 PMIDs, no full-text papers were retrieved (fulltext_map.json is empty; publications directory empty), OncoKB reports no variant-specific reviewed functional evidence (Unknown Oncogenic Effect), and the single ClinVar submission (Ambry Genetics, Uncertain significance, SCV005139027) provides no functional data, criteria, or PMIDs. The SpliceAI max delta score of 0.01 is an in-silico splice prediction and does not constitute a functional assay; absence of predicted splice impact cannot substitute for BS3. REVEL (0.914) and BayesDel (0.499) are in-silico and excluded from BS3. Absence of functional data cannot be interpreted as evidence of normal function, so BS3 is not met; with no functional study available in either direction, the criterion is not_assessed.
BS3 (generic ACMG/AMP 2015, PMID:25741868 via generic_acmg_combination_rules): Well-established functional studies showing no damaging effect; strong strength, requires a validated assay with controls. Not applicable in the absence of functional study evidence.
BS4 (Richards et al. 2015, PMID:25741868) is met when the variant is absent in an affected family member despite co-segregation being expected (lack of segregation in affected relatives) for a dominant disorder. The case bundle contains no family data whatsoever for NM_001033082.2:c.961C>G: no affected relatives tested, no non-segregation observations, no pedigree. ClinVar VCV003297294 provides only a single-submitter germline VUS with no family information, and no publications are available (0 PMIDs). Non-segregation evidence therefore cannot be evaluated; BS4 is not assessable. Governing framework: generic ACMG/AMP 2015 fallback (no MYCL CSPEC/VCEP exists).
generic ACMG/AMP 2015 (PMID:25741868) BS4 - requires lack of segregation in affected family members; not assessable without family segregation data
Generic ACMG/AMP 2015 BP2 ('observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder OR observed in cis with a pathogenic variant in any inheritance pattern') cannot be evaluated. No pathogenic variant in MYCL was identified in any source that could occupy the second allele in cis or trans: the only ClinVar record (variation 3297294) is a single-submitter Uncertain significance entry with no criteria, no PMIDs, and no phase information; gnomAD data are population frequencies only (no family or phase context); literature_pass.json reports 0 PMIDs and fulltext_map.json is empty. No family/pedigree, segregation, or allele-phase observations exist for this variant, and MYCL has no established fully-penetrant dominant germline disease association (pvs1_gene_context: inheritance [], germline context literature_only). Both arms of BP2 (trans with a pathogenic variant in a fully penetrant dominant disorder, or cis with a pathogenic variant) are unsupported by the available evidence. Insufficient evidence is recorded as not_assessed with the gap identified.
Generic ACMG/AMP 2015 (PMID:25741868) BP2: observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder OR observed in cis with a pathogenic variant in any inheritance pattern. No VCEP/CSPEC specification exists for MYCL (cspec found: false; framework_mode: generic_acmg; source: generic_acmg_combination_rules).
Generic ACMG/AMP 2015 (PMID:25741868) BP5 requires the variant to be found in a case with an alternate molecular basis for disease (e.g., a pathogenic variant in another gene fully explaining the phenotype, or another explanatory molecular cause). The case bundle contains no proband-level molecular data beyond this single variant: no other-gene findings, no panel/exome results, no proband phenotype, and no case narrative. The sole ClinVar submission (SCV005139027) has an empty conditions list and provides no case-level information. With no proband alternative-cause evidence either way, BP5 cannot be evaluated and is returned not_assessed.
Generic ACMG/AMP 2015 (PMID:25741868) BP5: 'A (likely) pathogenic variant in a gene that fully explains the phenotype exists in the proband (alternative cause at another locus).' Requires proband-level identification of an alternative molecular cause.
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_001033082.2:c.961C>G in MYCL is a missense substitution predicted to produce NP_001028254.2:p.(Arg321Gly). 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.
deterministic_prefilter: requires_null_variant_class
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_001033082.2:c.961C>G in MYCL is a missense substitution predicted to produce NP_001028254.2:p.(Arg321Gly). 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.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BS2 (Richards et al. 2015) requires observation in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. The criterion's prerequisite is an established monogenic disorder with a defined mode of inheritance and penetrance model; MYCL has no established germline monogenic disease (it is a somatic oncogene amplified in small cell lung cancer), so disease prevalence and penetrance cannot be evaluated. In addition, the observed population data show no support: 0 homozygotes in gnomAD v2.1 and v4.1, and only 1-4 heterozygous alleles in >1.6 million alleles. BS2 is therefore not applicable, and even under a hypothetical dominant model the observations would be insufficient to establish non-penetrance in healthy adult carriers.
generic_acmg: BS2 requires observation in healthy adults (homozygous recessive / heterozygous dominant with full penetrance at early age); prerequisite of an established disorder with defined penetrance is not met for MYCL
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001033082.2:c.961C>G in MYCL is a missense substitution predicted to produce NP_001028254.2:p.(Arg321Gly). 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.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001033082.2:c.961C>G in MYCL is a missense substitution predicted to produce NP_001028254.2:p.(Arg321Gly). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7'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.
deterministic_prefilter: requires_synonymous
Every interpreted variant in MYCL, mapped onto the exon structure of NM_001033082.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)4 / 1,180,042 | 3.4e-06 |
| European (non-Finnish)1 / 113,768 | 8.8e-06 |
This variant is present in gnomAD v4.1 (AF= 2.47801e-06; MAF= 0.00025%, 4/1614198 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38971e-06; MAF= 0.00034%, 4/1180042 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
This variant is present in gnomAD v2.1 (AF= 3.97624e-06; MAF= 0.00040%, 1/251494 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78982e-06; MAF= 0.00088%, 1/113768 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
Two independent missense in-silico tools both predict a deleterious effect. REVEL = 0.914 (local REVEL v1.3 lookup, chr1:39897596 G>C), far above standard pathogenic thresholds (0.5 supporting / 0.75 strong). BayesDel (noAF) = 0.499098, also above standard pathogenic thresholds. These constitute multiple lines of computational evidence supporting a deleterious effect on the gene product, meeting generic PP3. SpliceAI (max delta 0.01) predicts no splice impact, which does not contradict PP3 for a missense variant. Strength is set to supporting per the generic ACMG/AMP 2015 default (PMID 25741868) because MYCL has no VCEP/CSPEC specification; note that both tools individually exceed strong calibrated thresholds (e.g. Pejaver et al. 2022-style calibration), so PP3 could be upgraded if a MYCL-specific rule later formalizes calibration - this does not double-count, as it remains the same single criterion.
PP3 (Richards et al. 2015, PMID 25741868): multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.); supporting strength under generic ACMG/AMP.
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. The missense in-silico lines point in the opposite direction: REVEL 0.914 and BayesDel 0.499098 both predict a deleterious effect, directly contradicting a no-impact conclusion. The only potentially BP4-consistent line is SpliceAI (max delta 0.01, all four delta scores <= 0.01), which predicts no splice impact; however, a single splice predictor without concordant benign missense predictions does not satisfy the 'multiple lines' requirement of generic BP4, and the splice result does not address missense pathogenicity. BP4 is therefore not met.
BP4 (Richards et al. 2015, PMID 25741868): multiple lines of computational evidence suggest no impact on the gene or gene product; supporting strength under generic ACMG/AMP.
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001033082.2:c.961C>G in MYCL is a missense substitution predicted to produce NP_001028254.2:p.(Arg321Gly). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7'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.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.914. BayesDel score = 0.499098.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 2.47801e-06; MAF= 0.00025%, 4/1614198 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.38971e-06; MAF= 0.00034%, 4/1180042 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.
This variant is present in gnomAD v2.1 (AF= 3.97624e-06; MAF= 0.00040%, 1/251494 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.78982e-06; MAF= 0.00088%, 1/113768 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3297294)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.914. BayesDel score = 0.499098.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MYCL, a transcription factor, is altered by overexpression and amplification in various cancer types including small cell lung cancer.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.