MYC c.221C>G, p.(Pro74Arg)

Reasoning

No MYC-specific ClinGen VCEP/CSPEC framework is available (cspec.found=false in prefetch), so generic ACMG PM1 (mutational hotspot / functional domain lacking benign variation) is applied cautiously. OncoKB's variant-specific curated record for MYC P74R (not a gene-general summary) classifies the variant as 'Likely Oncogenic' with a curated biological effect of 'Likely Gain-of-function', indicating this exact residue/substitution has been specifically reviewed and flagged as a recurrent functionally relevant change in the MYC N-terminal transactivation region near the well-characterized T58/S62 phosphodegron hotspot. This is treated as supporting-level PM1 evidence only, reflecting that OncoKB curation of somatic oncogenicity is not a direct substitute for a germline mutational-hotspot statistic, and that the case's own cancerhotspots.org and COSMIC recurrence findings (which corroborate P74 as a statistically significant hotspot with 5 somatic COSMIC occurrences) could not be formally cited here because neither has a source_registry entry in this case bundle, only appearing inside evidence.json without a citation key.

Evidence considered

• OncoKB variant-specific page for MYC P74R (https://www.oncokb.org/gene/MYC/P74R) reports classification 'Likely Oncogenic' and biological_effect 'Likely Gain-of-function', explicitly is_variant_specific=true (not a gene-level summary).
• Case evidence.json (not independently citable) additionally records cancerhotspots.org flagging P74 as 'a statistically significant hotspot' and COSMIC recording 5 somatic occurrences of this exact change (COSV52375206) — used only as corroborating context, not as a formal evidence_ref.

Still missing

• cancerhotspots.org and COSMIC recurrence data corroborate a hotspot at residue P74 but have no source_registry citation key in this case bundle, so they could not be used as formal evidence_refs despite being directly relevant.
• The cancerhotspots.org scrape itself carries an explicit warning ('Regex extraction partial; verify screenshot'), so the hotspot statistical significance claim needs manual screenshot verification.
• No formal MYC-specific structural/functional domain boundary data (e.g., MYC Box I/II annotation) was available in this bundle to confirm p.Pro74 falls within a defined conserved functional domain.

Sources

Reasoning

PM2 is met under the generic fallback because NM_002467.6:c.221C>G is reported absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. The evidence supports rarity in reference populations, but confidence is moderated because the bundle lacks allele-number tables, ancestry-specific coverage details, disease prevalence and penetrance estimates, and an applicable MYC-specific VCEP framework.

Rule

Generic ACMG/AMP PM2: the variant is absent or extremely rare in population databases that are appropriate for the disease context; absence in the three queried datasets satisfies the available generic rarity evidence, subject to the stated data-quality gaps.

Evidence considered

• The case bundle reports the exact variant as absent from gnomAD v2.1.
• The case bundle reports the exact variant as absent from gnomAD v4.1.
• The case bundle reports the exact variant as absent from gnomAD-Canada v1.0.
• No applicable MYC-specific VCEP framework was found, so the generic ACMG/AMP population-evidence rule was used.

Still missing

• No exact allele counts, total allele numbers, coverage metrics, or ancestry-stratified results are provided in the bundle.
• No disease-specific maximum credible allele frequency, prevalence, or penetrance model is available.
• No MYC-specific VCEP/CSPEC specification was retrieved.

Sources

Reasoning

No governing VCEP/cSPEC framework was found for MYC (cspec.found=false; vcep_materials note='no cspec url available'), so generic ACMG/AMP computational-evidence rules apply. The variant NM_002467.6:c.221C>G / NP_002458.2:p.(Pro74Arg) is a missense substitution. Local REVEL lookup returns a score of 0.721, which falls within the ClinGen SVI-calibrated PP3_Supporting band (REVEL >=0.644 and <0.773) established in the published meta-predictor calibration (Pejaver et al. 2022, PMID 36413997). SpliceAI predicts no splice-altering effect (max delta = 0.00) for this exonic missense substitution, which is consistent with a purely missense mechanism and does not undermine using the missense (REVEL) computational path; SpliceAI is not itself invoked toward PP3 to avoid double counting the same prediction across PP3/BP4/BP7. BayesDel score (0.210026) was retrieved but is not used: no verified published calibration/threshold publication for BayesDel is available to this pipeline, so it is treated as not_available for PP3/BP4 per pipeline policy regardless of the numeric value.

Rule

Generic ACMG/AMP PP3 (REVEL calibrated per PMID 36413997; no MYC-specific VCEP PP3/BP4 lookup available)

Evidence considered

• REVEL score = 0.721 for NM_002467.6:c.221C>G (local REVEL v1.3 lookup), which falls in the PP3_Supporting range (>=0.644, <0.773) of the ClinGen SVI-recommended calibrated REVEL thresholds published by Pejaver et al. 2022 (PMID 36413997).
• SpliceAI max delta score = 0.00 (pangolin_SG=0.002, pangolin_SL=-0.004) indicates no predicted splice-altering effect, consistent with the variant acting through a missense mechanism rather than splicing; this observation was not separately counted toward PP3/BP4/BP7 to avoid double counting.
• No ClinGen MYC VCEP-specific PP3/BP4 lookup table was found (cspec.found=false; vcep_materials.summaries empty), so the generic ACMG/AMP REVEL-based approach was applied.

Still missing

• No official ClinGen MYC VCEP or gene-specific PP3/BP4 lookup spreadsheet was available in vcep_materials.json to override or refine the generic REVEL-based call.
• BayesDel score is present but cannot be used because no verified published calibration/threshold publication is available to this pipeline.

Sources

Reasoning

BA1 is not met because NM_002467.6:c.221C>G (MYC p.Pro74Arg) is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. No population allele frequency remotely approaches a stand-alone benign threshold.

Rule

Generic ACMG/AMP BA1: a population allele frequency at or above the stand-alone benign threshold is required; absence does not meet BA1.

Evidence considered

• The case bundle reports the exact variant as absent from gnomAD v2.1.
• The case bundle reports the exact variant as absent from gnomAD v4.1.
• The case bundle reports the exact variant as absent from gnomAD-Canada v1.0.

Still missing

• The bundle provides absence calls but no callable allele-number or ancestry-specific count tables.

Sources

Reasoning

BS1 is not met because the variant is absent from all three population resources evaluated. There is no observed allele frequency exceeding the disease-specific expected maximum or otherwise supporting a benign frequency interpretation.

Rule

Generic ACMG/AMP BS1: an allele frequency greater than expected for the disorder is required; no such frequency is observed.

Evidence considered

• The exact variant is reported absent from gnomAD v2.1, so no elevated population frequency supports BS1.
• The exact variant is reported absent from gnomAD v4.1, so no elevated population frequency supports BS1.
• The exact variant is reported absent from gnomAD-Canada v1.0, so no elevated population frequency supports BS1.

Still missing

• No disease prevalence, penetrance, allelic architecture, or gene-specific maximum credible allele frequency is established in the bundle.
• The bundle provides absence calls but no ancestry-specific allele-number tables.

Sources

Reasoning

BP1 applies when a missense variant occurs in a gene where disease is caused primarily by truncating/loss-of-function variants, making missense variants generally benign. The available variant-specific evidence for MYC p.Pro74Arg points the opposite direction: OncoKB's variant-level curation calls this specific missense change 'Likely Oncogenic' with a 'Likely Gain-of-function' biological effect, and case evidence additionally shows this exact residue is a recurrent somatic hotspot (COSMIC recurrence, cancerhotspots.org significance flag, though the latter two lack citable registry keys). This is inconsistent with a gene mechanism where missense variants are generically tolerated/benign, so BP1 is not met.

Evidence considered

• OncoKB variant-specific page for MYC P74R: classification 'Likely Oncogenic', biological_effect 'Likely Gain-of-function', is_variant_specific=true, indicating this missense change itself has functional/pathogenic significance rather than being a tolerated benign substitution.

Still missing

• No formal germline-specific missense-vs-truncating mechanism comparison for MYC was available in this bundle; conclusion rests on the oncogenic/gain-of-function OncoKB curation of this specific variant rather than a dedicated germline BP1 gene-mechanism study.

Sources

Reasoning

No governing VCEP/cSPEC framework was found for MYC, so generic ACMG/AMP computational-evidence rules apply. Because the missense computational path (REVEL = 0.721) falls in the pathogenic-supporting (PP3) band, BP4 (benign computational prediction) cannot also be applied for the same variant/mechanism - PP3 and BP4 are mutually exclusive directions of the same evidence axis. SpliceAI predicts no splice-altering effect (max delta = 0.00), but this null splicing result does not independently support BP4 for an exonic missense variant whose predicted mechanism (per REVEL) is damaging; it is merely consistent with the variant acting through a missense (not splicing) mechanism, not evidence of overall benign computational prediction.

Rule

Generic ACMG/AMP BP4 (mutually exclusive with PP3 on the missense/REVEL axis; SpliceAI null result insufficient alone; no MYC-specific VCEP lookup available)

Evidence considered

• SpliceAI max delta score = 0.00 (pangolin_SG=0.002, pangolin_SL=-0.004) shows no predicted splice-altering effect for NM_002467.6:c.221C>G, but this does not stand alone as benign computational evidence for a missense variant whose REVEL score (0.721) supports a pathogenic prediction.
• REVEL score = 0.721 falls in the PP3_Supporting range per ClinGen SVI-calibrated thresholds (Pejaver et al. 2022, PMID 36413997), precluding concurrent application of BP4 for the same missense computational axis.

Still missing

• SpliceAI's null splice-impact result was not usable to support BP4 given that the missense REVEL evidence already points toward the pathogenic direction (PP3); applying BP4 alongside PP3 for the same variant would double count/contradict the computational evidence axis.
• BayesDel score is present but cannot be used because no verified published calibration/threshold publication is available to this pipeline.

Sources

Reasoning

PS1 requires an established pathogenic variant producing the identical amino-acid change (p.Pro74Arg) at this codon via a different nucleotide substitution. This variant is absent from ClinVar entirely, and pm5_candidates.json (the same-residue comparator harvester) explicitly reports pm5_mode='unknown' and eligible_for_classic_pm5_search=false, instructing that no automated same-residue comparator search was performed and that PM5/PS1-adjacent conclusions should not be drawn from that artifact alone. No other source in the bundle provides a prior classified pathogenic variant at codon 74 with the same resultant amino acid.

Evidence considered

• ClinVar search for MYC[GENE] AND c.221C>G[VARNAME] returned no result (evidence_sentence: 'This variant is absent from ClinVar').
• pm5_candidates.json recommendation: 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting' with explicit instruction not to apply same-residue PM5/PS1-style conclusions from that artifact alone.

Still missing

• No ClinVar record exists for NM_002467.6:c.221C>G or any other variant at codon 74.
• pm5_candidates.json was explicitly not eligible for classic same-residue search; no comparator variant list was harvested to check for a same-amino-acid-change precedent.

Sources

Reasoning

No case-level evidence documents confirmed de novo occurrence of NM_002467.6:c.221C>G (NP_002458.2:p.(Pro74Arg)). The consolidated evidence bundle contains no proband-parent genotypes, parental testing results, maternity/paternity confirmation, or pedigree information. Therefore PS2 cannot be assessed.

Rule

Generic ACMG/AMP PS2: apply only when a variant is proven to have arisen de novo in the patient, with confirmed maternity and paternity; strength depends on the quality and number of de novo observations and phenotype consistency.

Evidence considered

• The consolidated case-evidence bundle provides variant normalization and population/database results but no documented de novo testing or parent-child genotype comparison.
• No applicable MYC-specific VCEP/CSPEC framework was available; generic ACMG/AMP criteria were therefore used.
• The available publication is an AML somatic cohort report and does not provide a de novo germline observation for this variant.

Still missing

• Proband genotype confirmation
• Both parental genotype results
• Confirmation of biological parentage or equivalent maternity/paternity evidence
• Assessment for parental mosaicism where relevant

Reasoning

No ClinGen VCEP/gene-specific framework exists for MYC (cspec.found=false, vcep_materials empty). No validated functional/biochemical assay data (e.g., transactivation, transformation, degradation, or luciferase reporter assays specific to p.Pro74Arg) were retrieved for this variant. The only literature hit, PMID:27276561 (Genomic Classification and Prognosis in AML), is a large clinical genomics cohort paper without any functional assay of MYC p.Pro74Arg and does not mention this variant or residue P74 anywhere in its full text. OncoKB provides a curated 'Likely Oncogenic'/'Likely Gain-of-function' label, but this is a computational/curatorial classification, not a validated functional assay with documented controls, replicates, or a defined normal/abnormal range, so it cannot substitute for PS3-grade functional evidence.

Evidence considered

• cspec.found=false and vcep_materials.json show no MYC-specific VCEP/CSPEC functional evidence framework was located.
• literature_pass.json/case_summary.json literature_packet lists exactly one PMID (27276561), themed 'functional' by the triage heuristic, but full-text search of /publications/27276561.txt for 'P74', 'Pro74', 'c.221C', and '221C>G' returned zero matches, indicating this AML cohort/prognosis paper does not report a functional assay of this specific variant.
• OncoKB evidence_sentence: 'biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic' is a database curation summary, not a documented wet-lab functional assay with assay type, controls, or replicate data, so it is insufficient to establish PS3.

Still missing

• No validated in vitro or in vivo functional assay (e.g., transformation, transactivation, degron/degradation, or transcriptional target assays) for MYC p.Pro74Arg was found in the retrieved literature.
• No gene-specific VCEP functional assay framework (PS3/BS3 strength calibration table) is available for MYC.
• OncoKB's Likely Oncogenic/Gain-of-function call is a curated annotation, not raw assay data with controls, so it cannot be used to satisfy PS3.

Reasoning

No germline case series, affected-proband count, or case-control enrichment data for NM_002467.6:c.221C>G (NP_002458.2:p.Pro74Arg) were identified. The available AML publication concerns somatic cancer genomics and does not establish phenotype prevalence or case-control enrichment for this exact germline variant.

Evidence considered

• The case bundle reports no ClinVar record, no VCEP/CSPEC framework, and no case-level phenotype or case-control evidence for this variant.
• The searched AML genomic cohort publication did not mention c.221C>G, p.Pro74Arg, or P74R and therefore cannot support PS4.

Still missing

• An exact-variant case series or case-control dataset with affected individuals and appropriate controls is unavailable.
• No validated quantitative enrichment threshold or VCEP-specific PS4 rule is available.

Sources

Reasoning

No applicable MYC-specific VCEP or gene-specific framework was available, so the generic ACMG/AMP PM3 rule was considered. The case bundle contains no affected-proband observations, parental or family phasing, inheritance information, or documented pathogenic/likely pathogenic variant in trans. The target variant is absent from ClinVar and population databases, but those findings do not establish PM3.

Rule

Generic ACMG/AMP PM3: pathogenic variant observed in trans with a pathogenic variant in an affected individual for a recessive disorder; apply only when phase and the pathogenic status of the other allele are adequately established.

Evidence considered

• The consolidated case-evidence bundle reports no MYC VCEP or gene-specific framework and falls back to generic ACMG/AMP.
• The bundle provides no family, proband, parental, phase, or second-allele observations relevant to PM3.
• Generic PM3 requires the variant to be observed in trans with a pathogenic variant in an affected individual for a recessive disorder; that required evidence is unavailable here.

Still missing

• Affected-proband or case-level evidence is not provided.
• A confirmed pathogenic or likely pathogenic second allele is not provided.
• Phase and inheritance are not provided; it is unknown whether any second variant is in trans.

Reasoning

PM5 requires a different missense change at the same codon (i.e., not p.Pro74Arg) previously established as pathogenic/likely pathogenic. pm5_candidates.json explicitly declares eligible_for_classic_pm5_search=false and pm5_mode='unknown', with the stated reason 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting,' and its hermes_instruction states that PM5 should not be applied from that artifact alone. No same-residue comparator variant search was independently available elsewhere in the bundle.

Evidence considered

• pm5_candidates.json: 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting'; candidate_summary shows total_candidates_seen=0, same_residue_candidates=0.

Still missing

• Automated same-residue comparator harvesting for PM5 was not performed for this case (pm5_candidates.json explicitly opted out), so no data exists to confirm or refute alternate pathogenic missense changes at codon 74.

Sources

Reasoning

No case-level evidence documents a suspected de novo occurrence of NM_002467.6:c.221C>G without confirmed maternity and paternity. The consolidated evidence bundle contains no parental testing results, pedigree information, or proband phenotype assessment. Therefore PM6 cannot be assessed.

Rule

Generic ACMG/AMP PM6: apply only for a suspected de novo occurrence when maternity and paternity are not confirmed, with appropriate phenotype consistency; it is weaker than PS2 because parentage or equivalent confirmation is incomplete.

Evidence considered

• The consolidated case-evidence bundle contains no suspected de novo family observation or parental testing data.
• No applicable MYC-specific VCEP/CSPEC framework was available; generic ACMG/AMP criteria were therefore used.
• The available publication is an AML somatic cohort report and does not provide a relevant suspected de novo germline observation.

Still missing

• Proband genotype confirmation
• Parental genotype or clinical testing information sufficient to establish suspected de novo status
• Phenotype consistency with a relevant MYC-associated disorder
• Clarification of whether maternity and paternity were confirmed

Reasoning

No familial segregation data are provided for NM_002467.6:c.221C>G. The consolidated evidence bundle contains no affected or unaffected relatives, informative meioses, pedigree, genotype-phenotype cosegregation, or family-based likelihood information. Therefore PP1 cannot be assessed at any strength.

Rule

Generic ACMG/AMP PP1: apply when a variant cosegregates with disease in affected family members; strength may increase with multiple informative meioses and robust phenotype ascertainment.

Evidence considered

• The consolidated case-evidence bundle contains no family segregation or genotype-phenotype cosegregation observations.
• No applicable MYC-specific VCEP/CSPEC framework was available; generic ACMG/AMP criteria were therefore used.
• The available publication is an AML somatic cohort report and does not provide family segregation evidence for this variant.

Still missing

• Pedigree and family structure
• Genotypes of affected and unaffected informative relatives
• Phenotype status and diagnostic criteria for each relative
• Number of informative meioses and segregation consistency

Reasoning

PP2 requires the gene to have a low rate of benign missense variation and missense to be a common mechanism of Mendelian disease. This bundle contains no gene-specific missense constraint metric (e.g., missense Z-score, ExAC/gnomAD missense observed/expected) for MYC, and the germline-disease literature review performed for PVS1 gating (pvs1_gene_context.json) did not return any publication actually discussing MYC germline disease; its 'supporting_papers' concern FBXW7, PMP22, APC, FOXP3, and SMARCA4, none of which mention MYC, so that artifact cannot establish whether missense variation is a recognized germline MYC disease mechanism. MYC's best-characterized disease role in this bundle is as a somatic oncogene (OncoKB/COSMIC/hotspots), which does not directly establish a germline PP2 missense-mechanism/benign-variation-rate profile.

Evidence considered

• pvs1_gene_context.json's five 'supporting_papers' (PMID:42111496, PMID:40488457, PMID:40702333, PMID:40962358, PMID:42279597) were reviewed and none discuss MYC germline missense disease mechanism; they concern FBXW7, PMP22, APC, FOXP3, and SMARCA4 respectively, so they cannot ground a PP2 assessment for MYC.

Still missing

• No missense constraint metric (e.g., gnomAD missense Z-score or o/e ratio) for MYC is present in this bundle.
• pvs1_gene_context.json's germline literature search did not return any MYC-specific germline missense disease publications despite claiming germline_disease_context_found=true; the cited supporting papers concern unrelated genes (FBXW7, PMP22, APC, FOXP3, SMARCA4) and cannot be used to establish a MYC missense disease mechanism.

Sources

Reasoning

No patient phenotype, disease-specific clinical description, or phenotype-to-gene specificity assessment was provided for the variant. PP4 cannot be evaluated.

Evidence considered

• The case bundle contains no affected-person phenotype or clinical findings for this variant.

Still missing

• A documented phenotype of an affected individual is required.
• The specificity of that phenotype for a MYC-related disorder must be established.

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion. The case bundle states that NM_002467.6:c.221C>G is absent from ClinVar, with no expert-panel assertion; therefore PP5 cannot be applied.

Rule

exact-variant ClinVar expert-panel assertion only

Evidence considered

• ClinVar search returned no exact record for NM_002467.6:c.221C>G; no expert-panel classification was present. Ordinary, aggregate, or non-expert assertions would not qualify for PP5 under the governing instruction.

Still missing

• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is available.

Sources

Reasoning

BS2 cannot be assessed from the available population evidence. The variant is absent from the queried population datasets, so there are no documented healthy adult homozygotes or unaffected adults carrying the variant to support BS2.

Rule

Generic ACMG/AMP BS2: observation in healthy adults, including homozygotes where relevant, is required; no such observation is documented.

Evidence considered

• The population resources report the variant as absent; absence is not evidence that healthy adults or homozygotes carry it.

Still missing

• No healthy adult carrier observations, homozygote observations, or phenotype follow-up data are available.
• No disease-specific penetrance and age-of-onset information is available to interpret unaffected carriers.

Sources

Reasoning

No ClinGen VCEP/gene-specific framework exists for MYC and no functional assay data (validated or otherwise) showing a normal/wild-type-like functional readout for p.Pro74Arg were retrieved. The single literature hit (PMID:27276561) does not mention this variant and is not a functional assay study. No basis exists to conclude the variant behaves as benign in a validated functional assay.

Evidence considered

• cspec.found=false; vcep_materials.json contains no MYC functional assay framework.
• Full-text search of PMID:27276561 for the variant/residue terms found no mention, confirming it is not a functional characterization source for this variant.
• OncoKB's evidence_sentence describes 'Likely Gain-of-function' (an abnormal, not benign, functional context), which is directionally inconsistent with BS3 and in any case is a curated annotation rather than raw assay data.

Still missing

• No functional assay data of any kind (showing normal or abnormal function) for MYC p.Pro74Arg were located in the retrieved evidence bundle or full-text literature.
• No gene-specific VCEP functional assay calibration table is available for MYC to define what would constitute a benign-range BS3 result.

Reasoning

No non-segregation evidence is available for NM_002467.6:c.221C>G. The consolidated evidence bundle does not identify unaffected informative relatives who were tested, their ages or phenotypes, the expected penetrance, or the number of informative meioses. Therefore BS4 cannot be assessed.

Rule

Generic ACMG/AMP BS4: apply when a variant is observed not to segregate with disease in affected family members or in appropriately informative family observations, accounting for penetrance, phenocopies, and phenotype ascertainment.

Evidence considered

• The consolidated case-evidence bundle contains no tested unaffected relatives or other documented non-segregation observations.
• No applicable MYC-specific VCEP/CSPEC framework was available; generic ACMG/AMP criteria were therefore used.
• The available publication is an AML somatic cohort report and does not provide relevant germline non-segregation evidence.

Still missing

• Genotyped unaffected informative relatives
• Reliable phenotype and age information for those relatives
• Expected disease penetrance and age-related expressivity
• Number and informativeness of non-segregating meioses

Reasoning

No applicable MYC-specific VCEP or gene-specific framework was available, so the generic ACMG/AMP BP2 rule was considered. The case bundle contains no affected-proband observations, parental or family phasing, inheritance information, or documented pathogenic/likely pathogenic variant in trans or cis. Therefore BP2 cannot be assessed.

Rule

Generic ACMG/AMP BP2: variant observed in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant for a recessive disorder; apply only when phase, pathogenic status of the other variant, and inheritance model are adequately established.

Evidence considered

• The consolidated case-evidence bundle reports no MYC VCEP or gene-specific framework and falls back to generic ACMG/AMP.
• The bundle provides no family, proband, parental, phase, or second-variant observations relevant to BP2.
• Generic BP2 requires observation of the variant with a pathogenic variant in trans for a dominant disorder, or in cis for a recessive disorder, with the relevant phase and inheritance context established; those data are unavailable here.

Still missing

• Affected-proband or case-level evidence is not provided.
• A confirmed pathogenic or likely pathogenic variant with which the target variant is observed is not provided.
• Phase is not provided, so trans or cis status cannot be determined.
• The applicable disease inheritance model is not established in the case evidence.

Reasoning

No affected patient with an alternative molecular etiology for the relevant phenotype was provided. BP5 cannot be evaluated from the available evidence.

Evidence considered

• The case bundle contains no clinical case description or alternative molecular diagnosis for an affected individual.

Still missing

• A documented affected individual and a confirmed alternative molecular cause explaining that individual's phenotype are required.

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel Benign or Likely benign assertion. The case bundle states that NM_002467.6:c.221C>G is absent from ClinVar, with no expert-panel assertion; therefore BP6 cannot be applied.

Rule

exact-variant ClinVar expert-panel assertion only

Evidence considered

• ClinVar search returned no exact record for NM_002467.6:c.221C>G; no expert-panel classification was present. Ordinary, aggregate, or non-expert assertions would not qualify for BP6 under the governing instruction.

Still missing

• No exact-variant ClinVar expert-panel Benign or Likely benign classification is available.

Sources