CCND1 c.844G>A, p.(Asp282Asn)

Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under the generic ACMG/AMP fallback, this supports PM2 because the variant is not observed in the available reference population datasets. The confidence is medium because dataset-level allele-number and ancestry-specific details are not present in the case bundle.

Rule

Generic ACMG/AMP PM2 supporting evidence is absence or extremely low frequency in population databases appropriate for the disorder; the variant is absent from all three available population datasets.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.

Still missing

• Allele-number and ancestry-stratified coverage details were not provided in the case bundle.
• No disease-specific maximum credible population frequency calculation was provided.

Sources

Reasoning

No governing ClinGen CSPEC/VCEP framework is available for CCND1 (cspec.found=false; generic_acmg fallback), so generic ACMG/AMP computational-evidence logic applies. NM_053056.3:c.844G>A (p.Asp282Asn) is missense, not synonymous, so BP7 is not applicable to this variant. On the splice-impact path, SpliceAI predicts no significant splice effect (max delta score = 0.001; all four delta scores <=0.001), strongly consistent with a benign splicing outcome. On the missense in-silico path, REVEL = 0.07 is well below the ClinGen SVI-calibrated REVEL benign-supporting threshold (REVEL <= 0.15-0.29 tiers per Pejaver et al. 2022, PMID 36413997), consistent with a benign functional prediction. Both the splice-impact and missense-impact computational lines of evidence concordantly support no functional impact, so BP4 is met at supporting strength (not upgraded to moderate/strong absent VCEP-specific calibration for CCND1). BayesDel score (-0.503138) was retrieved but is not used to support this call because no verified, citable published calibration threshold for BayesDel is available to this pipeline (per pipeline policy, treated as not_available regardless of its numeric value).

Rule

generic_acmg_bp4

Evidence considered

• SpliceAI (source_registry 'spliceai') max delta score = 0.001 for NM_053056.3:c.844G>A across DS_AG/DS_AL/DS_DG/DS_DL, indicating no predicted splice disruption.
• REVEL score = 0.07 (source_registry 'revel'), below the ClinGen SVI-calibrated REVEL benign-supporting thresholds described in Pejaver et al. 2022 (PMID 36413997).
• BayesDel score -0.503138 was retrieved (source_registry 'bayesdel') but excluded from this determination because no verified, citable published calibration threshold for BayesDel is available to this pipeline.

Still missing

• No CCND1-specific ClinGen VCEP PP3/BP4 lookup table available to check for a pre-assigned code or point-based combination.
• BayesDel score exists but cannot be applied without a named, citable calibration publication.

Sources

Reasoning

No governing ClinGen CSPEC/VCEP framework is available for CCND1 in this case (cspec.found=false; final_classification_framework.source=generic_acmg_fallback), so generic ACMG/AMP computational-evidence logic applies. NM_053056.3:c.844G>A is a missense variant (p.Asp282Asn). SpliceAI predicts no meaningful splice impact (max delta score = 0.001, DS_AG=0.0, DS_AL=0.0, DS_DG=0.001, DS_DL=0.0), far below any recognized 0.1-0.2 splice-altering threshold, so the splice-impact path does not support PP3. On the missense path, REVEL score is 0.07, well below the ClinGen SVI-calibrated pathogenic-supporting threshold (REVEL >= 0.644-0.773 tiers per PMID 36413997), so REVEL does not support a pathogenic prediction. BayesDel score (-0.503138) was also retrieved but per pipeline policy is treated as not_available for PP3/BP4 because no verified published threshold/citation is available to this pipeline; it is not used to call this criterion in either direction. No gene-specific VCEP PP3/BP4 lookup table exists for CCND1 (vcep_materials.summaries empty, files_found empty). With no in-silico evidence pointing toward a deleterious/splice-altering prediction, PP3 is not met.

Rule

generic_acmg_pp3

Evidence considered

• SpliceAI (via source_registry 'spliceai') max delta score = 0.001 for NM_053056.3:c.844G>A, indicating no predicted splice impact.
• REVEL score = 0.07 (via source_registry 'revel'), well below the ClinGen SVI-calibrated REVEL pathogenic-supporting thresholds described in Pejaver et al. 2022 (PMID 36413997).
• BayesDel score -0.503138 was retrieved (source_registry 'bayesdel') but is excluded from this determination because no verified, citable published calibration threshold for BayesDel is available to this pipeline.

Still missing

• No CCND1-specific ClinGen VCEP PP3/BP4 lookup table available to check for a pre-assigned code.
• BayesDel score exists but cannot be applied without a named, citable calibration publication.

Sources

Reasoning

The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0; therefore, there is no population frequency at or above a stand-alone benign threshold.

Rule

Generic ACMG/AMP BA1 requires a population allele frequency sufficiently high for a benign conclusion; no such frequency is observed in the available population datasets.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.

Sources

Reasoning

The variant is absent from the available population datasets, so it does not exceed a disease-specific or expected benign frequency threshold.

Rule

Generic ACMG/AMP BS1 requires an allele frequency greater than expected for the disorder; an absent variant cannot meet that frequency condition.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD v4.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.

Sources

Reasoning

PS1 requires a different nucleotide change at this codon that is already established as pathogenic while resulting in the identical amino acid change (Asp282Asn). ClinVar returned no records for NM_053056.3:c.844G>A or for CCND1 at this residue, and no CSPEC/VCEP framework was found for CCND1 to define PS1 application. No comparator variant data of any kind was retrieved for codon 282.

Evidence considered

• case_summary.json clinvar block: variant and gene searches at c.844G>A / codon 282 returned no ClinVar records ('This variant is absent from ClinVar'), so no established-pathogenic same-amino-acid-change comparator could be identified.

Still missing

• No ClinVar search results for CCND1 codon 282 (variant absent from ClinVar per clinvar source)
• No CCND1 VCEP/CSPEC framework available to define PS1 scope
• No literature identified reporting an alternate nucleotide change producing p.Asp282Asn as pathogenic

Sources

Reasoning

No proband-level de novo observation or parental testing result is documented in the consolidated case-evidence bundle. PS2 therefore cannot be assessed.

Rule

Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with confirmed maternity and paternity; stronger application requires appropriate phenotype and testing quality.

Evidence considered

• The consolidated case-evidence bundle identifies the variant as NM_053056.3:c.844G>A in CCND1 but contains no pedigree, proband genotype, parental testing, or de novo evidence.
• No applicable CCND1-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback is therefore applicable, but its PS2 requirements are not documented as met by this case evidence.

Still missing

• Documented alternate-allele presence in the proband
• Confirmed maternity and paternity
• Validated parental testing showing the variant absent from both biological parents
• Assessment of possible parental mosaicism

Reasoning

No ClinGen VCEP specification exists for CCND1 (cspec.found=false; final_classification_framework falls back to generic ACMG). No published functional/biochemical assay data (kinase activity, retinoblastoma-binding, proliferation, cell-cycle, or reporter assays) for NM_053056.3:c.844G>A p.(Asp282Asn) were identified: literature_pass.json returned zero PMIDs, ClinVar shows no submissions for this variant, and OncoKB explicitly states it found no variant-specific reviewed functional evidence for D282N (only generic gene-level context that CCND1 is amplified in various cancers). No publications directory content for this variant was reviewed as none were surfaced by the literature search. Without any well-validated assay data demonstrating an abnormal/damaging functional effect, PS3 cannot be applied.

Evidence considered

• case_summary.json cspec.found=false and final_classification_framework.found=false confirm no CCND1 VCEP specification is available, so generic ACMG applies for PS3/BS3.
• literature_pass.json: total_pmids=0, note='No PMIDs found across evidence sources' -- no functional-study literature was retrieved for this variant.
• evidence.json oncokb result: is_variant_specific=false, not_reviewed=true, classification='Unknown Oncogenic Effect'; evidence_sentence states OncoKB did not identify variant-specific reviewed functional evidence for D282N.
• evidence.json clinvar result: search_status='no_result', found=false -- no ClinVar submissions exist that might reference functional evidence for this variant.

Still missing

• No validated functional assay (e.g., cyclin D1/CDK4/6-Rb phosphorylation activity, proliferation, transformation, or cell-cycle assay) for p.(Asp282Asn) identified in the literature searched.
• No CCND1-specific VCEP PS3/BS3 assay calibration framework available to define strength or applicability.
• OncoKB annotation is gene-level only and explicitly not variant-specific.

Reasoning

No affected-case series, case-control comparison, enrichment analysis, or statistically supported disease-specific prevalence evidence for NM_053056.3:c.844G>A (NP_444284.1:p.Asp282Asn) was present in the case-evidence bundle.

Evidence considered

• The consolidated case-evidence bundle reports no literature PMIDs and contains no case-control or affected-case prevalence data for the exact variant.

Still missing

• Affected-case counts and matched control counts for this exact variant are unavailable.
• No case-control enrichment estimate, confidence interval, or statistical significance is available.

Reasoning

PM1 requires the variant to lie in a well-established mutational hotspot or critical/well-studied functional domain without benign variation. cancerhotspots.org returned no result for CCND1 D282, and no protein domain/structural annotation for this residue was captured in the evidence bundle. No CSPEC/VCEP framework exists for CCND1 to define domain boundaries or hotspot thresholds.

Evidence considered

• cancerhotspots.org search for 'CCND1 D282' returned no hotspot row (search_status: no_result); variant does not lie in a statistically significant hotspot per the site's data.
• OncoKB returned only gene-level context (CCND1 as a cell-cycle regulator amplified in various cancers) with no variant-specific or domain-specific functional annotation for D282N (classification: Unknown Oncogenic Effect, not variant-specific).

Still missing

• cancerhotspots.org query for CCND1 D282 returned no significant hotspot result
• No functional/structural domain annotation (e.g. UniProt, Pfam) for residue 282 was retrieved in this case's evidence set
• No CCND1 VCEP/CSPEC framework to define PM1 domain criteria
• OncoKB provided only gene-level (not variant- or domain-specific) annotation

Sources

Reasoning

No applicable CCND1-specific VCEP or gene-specific framework was available, so the generic ACMG/AMP PM3 concept applies. The case bundle contains no affected-proband observations, co-occurring pathogenic or likely pathogenic variants, phase information, parental testing, or inheritance-mode data establishing this variant in trans with a pathogenic variant for a recessive condition. PM3 cannot be assessed from the available evidence.

Evidence considered

• The consolidated case-evidence bundle identifies CCND1 and reports that no CSPEC/VCEP specification was found.
• The consolidated case-evidence bundle contains no family, phase, affected-proband, or second-allele observations relevant to PM3.

Still missing

• Affected-proband data and phenotype context are not provided.
• No pathogenic or likely pathogenic variant in the same gene is reported as a comparator allele.
• No cis/trans phase or parental segregation information is available.
• No applicable CCND1 inheritance model or gene-specific PM3 rule is established in the case materials.

Reasoning

PM5 requires a different missense change at the same residue (D282) previously established as pathogenic. The case's dedicated PM5 candidate-harvesting step explicitly flagged pm5_mode as 'unknown' and eligible_for_classic_pm5_search as false, returning zero candidates, with an explicit instruction not to apply PM5 from that artifact alone. ClinVar itself returned no records for this gene/residue.

Evidence considered

• pm5_candidates.json recommendation: level='not_applicable', summary='Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting', explicitly instructing reviewers not to apply PM5 from that artifact alone.
• ClinVar search for CCND1 c.844G>A and codon-282-adjacent queries returned no records (variant and gene/residue absent from ClinVar in this case).

Still missing

• pm5_candidates.json: eligible_for_classic_pm5_search=false, total_candidates_seen=0, same_residue_candidates=0 — automatic same-residue harvesting was skipped as unsafe
• No CCND1 VCEP/CSPEC framework to define PM5 semantics for this gene
• ClinVar search for CCND1 codon 282 alternate missense variants returned no results

Sources

Reasoning

No suspected de novo occurrence without confirmed maternity and paternity is documented in the consolidated case-evidence bundle. PM6 therefore cannot be assessed.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence, but without confirmation of maternity and paternity, in a patient with the disease and no family history.

Evidence considered

• The consolidated case-evidence bundle contains no family history, parental genotype, parentage, or suspected de novo report for NM_053056.3:c.844G>A.
• No applicable CCND1-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback is therefore applicable, but its PM6 requirements are not documented as met by this case evidence.

Still missing

• A documented patient with the relevant phenotype carrying the variant
• Evidence that the variant is absent from tested parents or arose de novo
• Maternity and paternity confirmation status
• Testing methodology and coverage for the parents

Reasoning

No affected or unaffected relatives, informative meioses, variant-positive relatives, or phenotype-segregation data are documented in the consolidated case-evidence bundle. PP1 cannot be assessed.

Rule

Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength depends on the number and informativeness of meioses.

Evidence considered

• The consolidated case-evidence bundle provides no segregation analysis, pedigree, family genotypes, affected-relative observations, or meiosis count for this variant.
• No applicable CCND1-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback is therefore applicable, but its PP1 requirements are not documented as met by this case evidence.

Still missing

• Pedigree with phenotype status for relevant relatives
• Genotypes of informative relatives
• Number of informative meioses
• Phenotype definition and consistency across variant-positive relatives
• Evaluation of possible phenocopies or reduced penetrance

Reasoning

PP2 requires the gene to have a low rate of benign missense variation and missense to be a common mechanism of disease for the associated Mendelian phenotype. No CCND1-specific VCEP/CSPEC framework or gene-level missense constraint/benign-rate statistic was captured in this case's evidence bundle to support this determination, and the gene-level PVS1 literature context in this case pertains to loss-of-function mechanism review rather than a missense-constraint analysis.

Still missing

• No CCND1 gene-level missense benign-rate or missense constraint metric (e.g. ClinGen/gnomAD missense Z-score, VCEP-defined benign missense rate) available in this bundle
• No CSPEC/VCEP framework for CCND1 to confirm whether missense is an established mechanism of the germline disease phenotype for PP2 purposes
• PVS1 gene-context literature in this case addresses LoF disease mechanism eligibility only, not a missense-specific PP2 determination

Reasoning

No patient phenotype, disease-specific clinical features, or phenotype specificity assessment was provided for this variant, so a highly specific phenotype cannot be evaluated.

Evidence considered

• The case-evidence bundle contains variant normalization and database results but no individual clinical phenotype or disease-specific presentation.

Still missing

• A detailed patient phenotype and confirmed clinical diagnosis are unavailable.
• No phenotype-to-disease specificity assessment is available.

Reasoning

PP5 is not applicable from the available ClinVar evidence because the exact variant has no ClinVar record and there is no ClinVar expert-panel Pathogenic or Likely pathogenic assertion.

Evidence considered

• ClinVar exact-variant lookup reported no result; therefore no expert-panel Pathogenic/Likely pathogenic assertion can support PP5.
• Ordinary laboratory submissions, aggregate labels, and non-expert assertions were not used for PP5.

Still missing

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

Sources

Reasoning

No reliable evidence was provided that the variant occurs in healthy adults, affected individuals with a clearly incompatible phenotype, or homozygous individuals without the relevant disease.

Rule

Generic ACMG/AMP BS2 requires observation of the variant in healthy adults or in homozygous individuals without the expected phenotype, with appropriate disease and penetrance context.

Still missing

• No phenotype-confirmed healthy-adult or disease-incompatible carrier observations were available.
• No homozygote observations or penetrance assessment were available.

Reasoning

No ClinGen VCEP specification exists for CCND1 (cspec.found=false), so generic ACMG applies. No functional assay data of any kind (damaging or benign-consistent) for NM_053056.3:c.844G>A p.(Asp282Asn) were located: literature_pass.json returned zero PMIDs, OncoKB found no variant-specific functional evidence, and ClinVar has no record for this variant. Without any well-established in vitro/in vivo assay showing normal/wild-type-like function, BS3 cannot be applied.

Evidence considered

• case_summary.json cspec.found=false and final_classification_framework.found=false confirm no CCND1 VCEP specification is available, so generic ACMG applies for PS3/BS3.
• literature_pass.json: total_pmids=0, note='No PMIDs found across evidence sources' -- no functional-study literature was retrieved for this variant.
• evidence.json oncokb result: is_variant_specific=false, not_reviewed=true -- no variant-specific functional data (damaging or benign) available.
• evidence.json clinvar result: search_status='no_result', found=false -- no ClinVar submissions with functional evidence exist for this variant.

Still missing

• No functional assay showing normal (wild-type-like) activity for p.(Asp282Asn) identified in the literature searched.
• No CCND1-specific VCEP BS3 assay calibration framework available.
• OncoKB annotation is gene-level only and explicitly not variant-specific, providing no benign functional signal either.

Reasoning

No non-segregation observation is documented. The consolidated case-evidence bundle does not identify an unaffected relative who carries the variant with adequate phenotype evaluation, so BS4 cannot be assessed.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected members of a family, or presence of the variant in unaffected family members, when the phenotype and penetrance are sufficiently established for interpretation.

Evidence considered

• The consolidated case-evidence bundle contains no unaffected carrier, non-segregation, pedigree, or family-genotyping evidence for NM_053056.3:c.844G>A.
• No applicable CCND1-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP fallback is therefore applicable, but its BS4 requirements are not documented as met by this case evidence.

Still missing

• Unaffected relatives with reliable clinical evaluation
• Genotype results for those relatives
• Age and ascertainment sufficient to interpret unaffected status
• Assessment of age-dependent penetrance and phenocopies

Reasoning

BP1 requires the gene's disease mechanism to be predominantly loss-of-function/truncating such that a missense variant is unlikely to be pathogenic. No CCND1-specific VCEP/CSPEC framework or gene-level mechanism statistic addressing this was available; this is the mirror determination to PP2 and equally unsupported by the current evidence bundle.

Still missing

• No CCND1 gene-level data establishing that missense variants are not a recognized mechanism of disease (needed to support BP1)
• No CSPEC/VCEP framework for CCND1 to define BP1 applicability
• This case's gene-context literature search targeted LoF mechanism plausibility for PVS1, not a BP1-specific missense-rarity determination

Reasoning

No applicable CCND1-specific VCEP or gene-specific framework was available, so the generic ACMG/AMP BP2 concept applies. The case bundle contains no evidence that this variant is observed in cis or trans with a pathogenic or likely pathogenic variant, and no inheritance or phase information is available. BP2 cannot be assessed from the available evidence.

Evidence considered

• The consolidated case-evidence bundle identifies CCND1 and reports that no CSPEC/VCEP specification was found.
• The consolidated case-evidence bundle contains no allelic co-occurrence, phase, family, or inheritance observations relevant to BP2.

Still missing

• No pathogenic or likely pathogenic variant in the same individual is reported.
• No cis/trans phase information is available.
• No affected/unaffected status or inheritance data are available to interpret a second allele.
• No applicable CCND1-specific BP2 rule is established in the case materials.

Reasoning

No evidence was provided that an alternative molecular diagnosis explains the relevant phenotype, and no patient phenotype is available against which such an alternative diagnosis could be evaluated.

Evidence considered

• The case-evidence bundle contains no alternative-diagnosis evidence for this patient.

Still missing

• A confirmed alternative molecular diagnosis or clearly established competing cause is unavailable.
• The patient's phenotype and diagnostic workup are unavailable.

Reasoning

BP6 cannot be applied because the exact variant has no ClinVar record and there is no ClinVar expert-panel Benign or Likely benign assertion.

Evidence considered

• ClinVar exact-variant lookup reported no result; therefore no expert-panel Benign/Likely benign assertion can support BP6.
• Ordinary laboratory submissions, aggregate labels, and non-expert assertions were not used for BP6.

Still missing

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

Sources