CDK4 c.122A>G, p.(Asn41Ser)

Reasoning

PM2 is met at supporting strength. The variant is rare in population databases: gnomAD v4.1 overall AF is 0.000253407 (0.02534%) with no homozygotes, and gnomAD v2.1 overall AF is 0.000113153 (0.01132%) with no homozygotes. The highest observed subpopulation frequency in gnomAD v4.1 is 0.000659848 (0.06598%), still below the generic rare-variant cutoff of 0.1% used here. It is also absent from gnomAD-Canada v1.0.

Rule

Generic population rule in the absence of a CDK4-specific VCEP specification: PM2 supporting may be applied when the variant is absent or extremely rare in appropriate population databases; this assessment uses a maximum observed allele-frequency cutoff below 0.1% and requires no homozygotes for this dominant disease context.

Evidence considered

• gnomAD v4.1 reports 409/1,614,004 alleles, overall AF 0.000253407 (0.02534%), highest subpopulation AF 0.000659848 (0.06598%), and 0 homozygotes.
• gnomAD v2.1 reports 32/282,802 alleles, overall AF 0.000113153 (0.01132%), highest subpopulation AF 0.000276932 (0.02769%), and 0 homozygotes.
• gnomAD-Canada v1.0 reports the variant as absent.
• The maximum observed subpopulation AF remains below the generic PM2 rare-variant cutoff of 0.1% used in this no-VCEP fallback assessment.

Still missing

• No CDK4-specific VCEP population rule or disease-specific maximum credible population frequency was available; assessment uses the generic fallback threshold.

Sources

Reasoning

No CDK4-specific VCEP PP3/BP4 lookup material or CSPEC exists (framework_mode=generic_acmg fallback), so generic ACMG/AMP combined with well-established published calibrated thresholds was applied. REVEL score = 0.113, which falls at or below the Pejaver et al. 2022 (PMID 36413997) ClinGen SVI-recommended benign-supporting/moderate cutoff (REVEL <=0.183 for BP4_Moderate; REVEL <=0.290 for BP4_Supporting), supporting a benign-leaning missense in silico prediction at moderate strength. This is corroborated by SpliceAI, which predicts no significant splice impact for this variant (max delta score = 0.061, well under the 0.2 splice-impact threshold), consistent with no alternate splice-disruptive mechanism. Both predictions point the same direction (benign) and are not stacked for extra strength; REVEL is used as the primary calibrated basis for BP4 strength with SpliceAI as corroborating, non-stacked evidence.

Rule

Generic ACMG/AMP 2015 BP4 combined with published calibration: REVEL threshold from Pejaver et al. 2022 (PMID 36413997), applied at Moderate strength (REVEL <=0.183). SpliceAI 0.2 delta-score threshold used as corroborating (non-stacked) splice evidence. No CDK4-specific VCEP PP3/BP4 table available to override this determination.

Evidence considered

• REVEL score = 0.113 (source_registry key 'revel') is below the Pejaver et al. 2022 (PMID 36413997) ClinGen SVI-recommended BP4_Moderate threshold of REVEL <=0.183, supporting BP4 at moderate strength.
• SpliceAI predicts no significant splice impact for this variant (max delta score = 0.061; DS_AG 0.005, DS_AL 0.061, DS_DG 0.004, DS_DL 0.023), below the 0.2 splice-impact threshold, corroborating a benign in silico prediction without an alternate splice mechanism.

Still missing

• No gene-specific VCEP PP3/BP4 lookup spreadsheet exists for CDK4 to directly pre-assign this code; strength was derived from published REVEL calibration (PMID 36413997) rather than a VCEP-specific table.
• BayesDel score (-0.569204) is present in prefetch data but excluded from this determination because no verified, citable published calibration threshold for BayesDel is available to this pipeline.

Sources

Reasoning

The only mutational-cluster/hotspot data available in the bundle are negative: cancerhotspots.org returned 'no_result' with the explicit evidence sentence that this variant does not lie in a statistically significant hotspot, and COSMIC shows only a single somatic observation (COSV104562019, n=1), well below any threshold suggestive of a recurrent hotspot. No CSPEC/VCEP-defined critical functional domain boundaries for CDK4 (e.g., kinase active site, ATP-binding loop, p16INK4a-binding interface) are present in this bundle to evaluate whether residue 41 falls within a well-established functional domain, so the domain arm of PM1 cannot be independently confirmed, but the hotspot arm is explicitly negative and there is no positive domain evidence to counterbalance it.

Evidence considered

• evidence.json hotspots result: search_status='no_result', found=false, evidence_sentence='This variant does not lie in a statistically significant hotspot.' (cancerhotspots.org, not present as a citable source_registry key).
• evidence.json cosmic result: found=true, evidence_sentence='This variant has previously been reported in somatic cancers (COSMIC; COSV104562019, n = 1 times).' — a single somatic observation, not indicative of a mutational hotspot (COSMIC entry likewise not present as a citable source_registry key).

Still missing

• No structural/domain annotation (e.g., UniProt/Pfam CDK4 kinase domain boundaries, p16INK4a-binding interface residues) was retrieved in this pass to assess whether residue 41 lies in a critical, well-established functional domain lacking benign variation.

Reasoning

No governing VCEP/gene-specific PP3/BP4 lookup material exists for CDK4 (vcep_materials.json: no cspec url available, framework_mode=generic_acmg, precedence_rank=3 fallback). Both available calibrated computational predictors point away from a damaging effect rather than toward one, so PP3 (pathogenic in silico evidence) is not met. REVEL = 0.113, far below any pathogenic-supporting cutoff (Pejaver et al. 2022, PMID 36413997: pathogenic-supporting requires REVEL >=0.644). SpliceAI max delta score = 0.061 (DS_AL 0.061, all other delta scores <=0.023), well under the ClinGen SVI-adopted 0.2 splice-impact threshold, so no splice-altering effect is predicted. BayesDel score (-0.569204) is available in prefetch data but is not used for this determination because no verified published calibration/threshold for BayesDel is available to this pipeline.

Rule

Generic ACMG/AMP 2015 PP3 combined with published calibration: REVEL threshold from Pejaver et al. 2022 (PMID 36413997); SpliceAI 0.2 delta-score splice-impact threshold. No CDK4-specific VCEP PP3/BP4 table available to override.

Evidence considered

• REVEL score = 0.113 (source_registry key 'revel'; local REVEL v1.3 lookup) — below the Pejaver et al. 2022 (PMID 36413997) ClinGen SVI-recommended pathogenic-supporting threshold of REVEL >=0.644, so does not support PP3.
• SpliceAI predicts no significant splice impact for this variant: max delta score = 0.061 (DS_AG 0.005, DS_AL 0.061, DS_DG 0.004, DS_DL 0.023), below the 0.2 splice-impact threshold, so does not support a splice-based PP3 pathway.

Still missing

• No gene-specific (VCEP) PP3/BP4 lookup spreadsheet or CSPEC exists for CDK4 in this case; generic ACMG combined with published REVEL/SpliceAI calibration was used instead.
• BayesDel score is present in the evidence bundle but withheld from adjudication because no named, citable published threshold for BayesDel is available to this pipeline.

Sources

Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The exact variant is present in ClinVar, but the bundle records zero expert-panel submissions; available assertions are ordinary laboratory submissions and the aggregate record is conflicting. PP5 is not met.

Rule

Apply PP5 only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar variation 135822 exactly matches NM_000075.4(CDK4):c.122A>G (p.Asn41Ser), but expert_panels is empty and the submission audit reports expert_panel_submissions = 0. The record contains only non-expert laboratory assertions, including Likely benign, Benign, and Uncertain significance, with conflicting aggregate classification.

Sources

Reasoning

BA1 is not met. The variant is present in gnomAD v4.1 at an overall allele frequency of 0.000253407 (0.02534%), with a maximum reported subpopulation frequency of 0.000659848 (0.06598%), which is below the generic benign stand-alone threshold of 1% used here when no applicable VCEP specification is available.

Rule

Generic population rule in the absence of a CDK4-specific VCEP specification: BA1 requires allele frequency greater than 1%.

Evidence considered

• gnomAD v4.1 reports 409/1,614,004 alleles, overall AF 0.000253407 (0.02534%), and the highest observed subpopulation AF is 0.000659848 (0.06598%) in the Middle Eastern population.
• gnomAD v2.1 reports 32/282,802 alleles, overall AF 0.000113153 (0.01132%), and the highest observed subpopulation AF is 0.000276932 (0.02769%).
• These frequencies are far below the generic BA1 threshold of 1%; no gene-specific CDK4 VCEP rule was available in this case.

Sources

Reasoning

BS1 is not met. The highest observed gnomAD v4.1 subpopulation frequency is 0.000659848 (0.06598%), below the generic BS1 threshold of 0.3% used here. The observed frequency therefore does not exceed the benign frequency threshold, even without relying on uncertain disease prevalence or penetrance estimates.

Rule

Generic population rule in the absence of a CDK4-specific VCEP specification: BS1 requires an allele frequency greater than 0.3% and compatible with a benign interpretation for the disease context.

Evidence considered

• gnomAD v4.1 reports an overall AF of 0.000253407 (0.02534%) and a maximum subpopulation AF of 0.000659848 (0.06598%) in the Middle Eastern population.
• gnomAD v2.1 reports an overall AF of 0.000113153 (0.01132%) and a maximum subpopulation AF of 0.000276932 (0.02769%).
• All observed frequencies are below the generic BS1 threshold of 0.3%; no applicable CDK4-specific frequency or disease-prevalence rule was retrieved.

Sources

Reasoning

BS2 is not met. gnomAD shows zero homozygotes for the variant in both v2.1 and v4.1, and the case bundle does not provide a documented series of multiple phenotypically healthy adult carriers with adequate age, phenotype, penetrance, and ascertainment information. Population-database heterozygote observations alone do not establish the BS2 healthy-adult criterion.

Rule

Generic ACMG/AMP BS2 requires observation of the variant in healthy adults in a disease expected to show full penetrance by adulthood, or observation of homozygotes without disease for a dominant condition; population allele counts alone are insufficient.

Evidence considered

• gnomAD v4.1 reports 0 homozygotes among 1,614,004 alleles.
• gnomAD v2.1 reports 0 homozygotes among 282,802 alleles.
• The available population records do not document individual ages, clinical phenotypes, ascertainment, or penetrance for the heterozygous carriers; therefore they cannot independently establish BS2.

Sources

Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The exact variant is present in ClinVar, but the bundle records zero expert-panel submissions; the Benign and Likely benign assertions are from ordinary laboratories and cannot trigger BP6.

Rule

Apply BP6 only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify.

Evidence considered

• ClinVar variation 135822 exactly matches NM_000075.4(CDK4):c.122A>G (p.Asn41Ser), but expert_panels is empty and the submission audit reports expert_panel_submissions = 0. The Benign and Likely benign classifications are non-expert single-submitter laboratory assertions and the aggregate record is conflicting.

Sources

Reasoning

PS1 requires an established pathogenic variant that produces the identical amino acid change (p.Asn41Ser) via a different nucleotide substitution. No CSPEC/VCEP is available for CDK4 (cspec.found=false), and neither the ClinVar record for this variant (VCV000135822) nor the pm5_candidates comparator search in this bundle identified any other nucleotide change resulting in p.(Asn41Ser). No same-amino-acid-change comparator evidence is present in the bundle.

Evidence considered

• case_summary.json cspec.found = false; no CDK4 VCEP/CSPEC specification available to define PS1 comparator rules.
• pm5_candidates.json indicates the automated same-residue comparator harvesting pipeline was disabled for this variant ('Unable to confirm classic same-residue PM5 semantics safely'), so the adjacent PS1 same-amino-acid-change search was likewise not completed in this pass.

Still missing

• No dedicated search for alternate codon changes producing p.(Asn41Ser) with an established pathogenic classification was performed/returned in this pass; a manual ClinVar/literature search for other c.122A>G-equivalent codon changes at residue 41 is needed.

Reasoning

No case-level evidence documents a confirmed de novo occurrence of NM_000075.4:c.122A>G (p.Asn41Ser), including proband status with verified maternity and paternity. The consolidated evidence bundle contains no parental testing results or de novo family observations.

Rule

Generic ACMG/AMP PS2: confirmed de novo occurrence in the patient with maternity and paternity confirmed; apply strength only when the de novo observation and phenotype are adequately documented.

Evidence considered

• The case summary identifies the variant as NM_000075.4:c.122A>G in CDK4 and reports no case-level parental testing or de novo evidence.
• ClinVar records the exact variant but provides conflicting laboratory classifications without documented parental testing or a confirmed de novo observation; a database classification was not used as PS2 evidence.

Still missing

• Proband phenotype and clinical indication are not documented in the available case-evidence bundle.
• Maternal and paternal relationships are not documented as genetically confirmed.
• Parental testing results for the variant are absent.
• No independent de novo observations or validated publication-level de novo reports for this exact variant are available.

Reasoning

No CDK4-specific VCEP/CSPEC is available for this case (framework_mode=generic_acmg, cspec.found=false), so generic ACMG applies. No validated functional assay (e.g., kinase activity, Rb phosphorylation, cell proliferation/complementation assay) specifically testing NM_000075.4:c.122A>G (p.Asn41Ser) was identified in the case bundle. The literature_pass criteria_index nominally lists PMID:19139070 and PMID:26252490 under PS3, but on inspection PMID:19139070 is a genome-wide bioinformatic phosphorylation-site prediction study and PMID:26252490 is an in silico molecular modelling/dynamics study of CDK4 inhibitors -- neither reports a wet-lab functional assay of this variant, and neither has confirmed full-text mentioning the variant. PMID:14621993 (IkappaBalpha-CDK4 kinase inhibition) and PMID:16201750 (p34(SEI-1)/p16(INK4A) CDK4-binding dissection) are gene-level protein-interaction/kinase studies of wild-type CDK4 with no mention of N41S/Asn41Ser in their full text, so they do not constitute variant-specific functional evidence.

Still missing

• No validated functional assay (kinase activity, Rb phosphorylation, cell-cycle/proliferation assay, or complementation assay) has been performed on p.Asn41Ser specifically.
• No CDK4 VCEP CSPEC available to define assay validation/control requirements for this gene.

Reasoning

No applicable CDK4-specific VCEP specification was retrieved, so generic ACMG/AMP was considered. The bundle does not provide an exact-variant case-control enrichment analysis or a validated count of unrelated affected individuals carrying NM_000075.4:c.122A>G (p.Asn41Ser) compared with controls. The reviewed colorectal-cancer cohort reports gene-level mutation prevalence and does not report this exact CDK4 variant; therefore PS4 cannot be applied.

Rule

Generic PS4 requires a statistically significant excess of affected individuals with the exact variant relative to controls, or equivalent validated case enrichment; gene-level prevalence and non-exact variant observations are insufficient.

Evidence considered

• PMID:28135145 was reviewed as a large clinical cohort of 1,058 individuals with colorectal cancer; it reports gene-level cancer-susceptibility mutation prevalence and lists CDK4 among genes examined, but its tables do not report NM_000075.4:c.122A>G or p.Asn41Ser and it is not an exact-variant case-control enrichment analysis.

Still missing

• An exact-variant case-control dataset with affected-carrier and control counts, or a sufficiently documented series of unrelated affected individuals carrying NM_000075.4:c.122A>G, is unavailable.

Sources

Reasoning

No applicable CDK4-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework was used. The case bundle contains no affected-proband observation of NM_000075.4:c.122A>G in a recessive disorder, no second pathogenic/likely pathogenic variant, and no parental or read-based phasing establishing the variants in trans. ClinVar submission metadata identifies germline records but does not provide the allelic phase or affected-proband genotype needed to apply PM3.

Rule

Generic ACMG/AMP PM3: apply only when the variant is observed in trans with a pathogenic variant in an affected individual with a recessive disorder, with strength determined by the number and quality of independent observations; phase and disease relevance must be established.

Evidence considered

• The case bundle reports an exact ClinVar match for NM_000075.4(CDK4):c.122A>G (p.Asn41Ser), with germline origins represented among submissions, but it contains no affected-proband genotype, second pathogenic allele, or phase information.
• The governing framework section states that no CDK4-specific CSPEC/VCEP framework was found; generic ACMG/AMP fallback therefore applies.

Still missing

• Affected-proband genotype and clinical phenotype relevant to a recessive CDK4 disorder are not provided.
• No pathogenic or likely pathogenic second allele is documented for this case.
• No parental, family, or molecular phasing establishes trans configuration.

Sources

Reasoning

The pm5_candidates.json artifact explicitly disabled automated same-residue comparator harvesting for this variant, flagging that classic PM5 semantics could not be safely confirmed, and returned zero same-residue candidates (same_residue_candidates=0, total_candidates_seen=0). Its own recommendation level is 'not_applicable' with an explicit instruction not to apply PM5 from that artifact alone, and no independent manual comparator search for other pathogenic/likely pathogenic amino acid changes at codon 41 (e.g., p.Asn41Lys, p.Asn41Ile, p.Asn41Thr) is present elsewhere in the bundle.

Evidence considered

• pm5_candidates.json: pm5_mode='unknown', eligible_for_classic_pm5_search=false, reason='Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting.', candidate_summary shows 0 total/same-residue candidates, recommendation.level='not_applicable' with instruction not to apply PM5 from this artifact alone.

Still missing

• A manual ClinVar/HGMD search for other reported missense changes at CDK4 codon 41 with an established pathogenic classification has not been performed within this evidence set.

Sources

Reasoning

No case-level or publication-level evidence documents a presumed de novo occurrence of NM_000075.4:c.122A>G (p.Asn41Ser) with sufficient phenotype and family context. The consolidated evidence bundle contains no parental testing results or reported de novo proband observation for this exact variant.

Rule

Generic ACMG/AMP PM6: assumed de novo occurrence when maternity and paternity are not confirmed; apply only when a credible clinical de novo observation and phenotype context are documented.

Evidence considered

• The available case evidence contains population, database, computational, and somatic observations but no documented presumed de novo clinical observation.
• The exact-variant literature trail in the bundle does not provide a verified de novo family report suitable for PM6.

Still missing

• No presumed de novo proband report for the exact variant is documented.
• Parental phenotypes and testing are absent.
• The proband phenotype and its consistency with a CDK4-related condition are not documented.
• No meiosis or family-history information is available.

Reasoning

No affected relatives, unaffected relatives, informative meioses, or genotype-phenotype segregation results are provided for NM_000075.4:c.122A>G (p.Asn41Ser). Therefore, cosegregation cannot be evaluated.

Rule

Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members, with strength determined by the number and informativeness of meioses and the phenotype specificity.

Evidence considered

• The consolidated case-evidence bundle contains no family pedigree, affected-relative testing, unaffected-relative testing, or segregation analysis for the exact variant.
• Literature references in the bundle were not used for PP1 because none was verified to report segregation of this exact variant.

Still missing

• No pedigree or family structure is available.
• No relatives with documented phenotype and variant status are reported.
• No informative meioses or segregation counts are available.
• No CDK4-related phenotype assessment is available for proband or relatives.

Reasoning

PP2 requires establishing that missense variants are a common mechanism of disease for CDK4 and that benign missense variation is rare. No CSPEC/VCEP specification is available (cspec.found=false) to confirm PP2 applicability for CDK4, and no gene-level missense constraint metric (e.g., missense Z-score, o/e ratio, ClinGen gene-disease validity curation) is present anywhere in the bundle. The only variant-level signal available is that this specific variant (p.Asn41Ser) has a split ClinVar submission history including a substantial Likely benign/Benign component (5+2 of 16 submitters), but that reflects only this single variant's own classification landscape, not a gene-wide missense benign-variation rate, and per instructions a criterion must not be inferred from another source's final classification.

Evidence considered

• case_summary.json cspec.found = false; no CDK4 VCEP/CSPEC guidance on PP2 applicability is available.
• No missense constraint/Z-score or ClinGen gene-disease validity artifact is present anywhere in the criteria_evidence_bundle for CDK4.

Still missing

• No CDK4 missense constraint metric (e.g., gnomAD missense o/e or Z-score) or ClinGen gene-disease validity classification was retrieved in this pass to support or refute PP2 applicability at the gene level.

Reasoning

No patient-specific phenotype, highly specific clinical presentation, or well-established CDK4-related phenotype matching this case is provided in the evidence bundle. A ClinVar single-submitter signal referring to colorectal cancer is not a validated patient phenotype and cannot establish phenotype specificity for this exact variant. PP4 therefore cannot be applied.

Rule

Generic PP4 requires a patient phenotype or family history highly specific for a disease associated with the gene; nonspecific cancer diagnoses, submission-derived signals, and absent case phenotype are insufficient.

Evidence considered

• The ClinVar evidence is an aggregate record with conflicting submissions and includes a low-confidence single-submitter phenotype signal related to colorectal cancer; it does not provide a validated patient phenotype or a specific CDK4 phenotype match for this case.

Still missing

• Documented phenotype and diagnostic details for the evaluated patient are unavailable.
• A well-established, highly specific CDK4-related disease phenotype matched to this patient is unavailable.

Sources

Reasoning

No CDK4-specific VCEP/CSPEC is available for this case (framework_mode=generic_acmg, cspec.found=false), so generic ACMG applies. No functional assay data (well-established, validated system) showing no damaging effect of NM_000075.4:c.122A>G (p.Asn41Ser) on CDK4 kinase function was identified. The functional-themed papers retrieved via ClinVar citation trail (PMID:14621993, PMID:16201750) study wild-type CDK4 protein interactions/kinase activity and do not test this specific missense variant; PMID:19139070 and PMID:26252490 are bioinformatic/in silico studies, not functional assays with normal-range readouts for this variant.

Still missing

• No functional assay data (variant-specific, with appropriate positive/negative controls) demonstrating normal CDK4 activity for p.Asn41Ser is available.
• No CDK4 VCEP CSPEC available to define assay validation/control requirements for this gene.

Reasoning

No informative unaffected relatives with reliable phenotype assessment and confirmed absence of NM_000075.4:c.122A>G (p.Asn41Ser) are documented. Non-segregation cannot be established from the available evidence.

Rule

Generic ACMG/AMP BS4: lack of segregation in affected family members or presence of the variant in unaffected family members when phenotype, age, and testing are sufficiently informative.

Evidence considered

• The case summary and evidence bundle do not document affected or unaffected relatives with variant testing and phenotype follow-up.
• Population frequency and conflicting ClinVar classifications do not constitute BS4 non-segregation evidence and were not used for this criterion.

Still missing

• No pedigree or relatives with documented disease status are available.
• No confirmed variant-negative affected relatives are reported.
• Age, surveillance, and phenotype data for potentially unaffected relatives are absent.
• No family-based non-segregation analysis is available.

Reasoning

BP1 requires establishing that primarily truncating variants (not missense) are the known disease mechanism for CDK4, which would make a missense finding like this one less likely pathogenic by that specific mechanism argument. No CSPEC/VCEP specification is available (cspec.found=false) confirming or excluding this designation for CDK4, and the pvs1_gene_context.json artifact in this bundle is not usable grounding here: its 'disease_names' and lead supporting literature (PMID:37509701) concern an unrelated ATM nonsense-variant family report co-tested on the same gene panel, not a CDK4-specific loss-of-function mechanism statement, so it cannot be relied upon to establish or refute a truncating-variant disease mechanism for CDK4.

Evidence considered

• case_summary.json cspec.found = false; no CDK4 VCEP/CSPEC guidance on BP1 applicability is available.
• pvs1_gene_context.json's lof_mechanism_supported=true determination is grounded in a supporting paper (PMID:37509701) about an ATM nonsense variant identified on a shared multigene cancer panel, not a CDK4-specific germline truncating-variant mechanism study, so it was not used to ground BP1 for CDK4.

Still missing

• No CDK4-specific, gene-level statement of disease mechanism (missense/gain-of-function vs. truncating/loss-of-function) grounded in a citable source is present in this bundle; the pvs1_gene_context.json supporting literature is mismatched (concerns ATM) and cannot be used for this determination.

Reasoning

No applicable CDK4-specific VCEP/CSPEC framework was retrieved, so the generic ACMG/AMP framework was used. The case bundle contains no documented observation of NM_000075.4:c.122A>G in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder. It also provides no affected/unaffected individual genotype, inheritance information, or phase determination; therefore BP2 cannot be applied.

Rule

Generic ACMG/AMP BP2: apply when the variant is observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant for a recessive disorder; the inheritance model, comparator variant, and phase must be established.

Evidence considered

• The case bundle reports ClinVar submissions for the exact variant but does not report a comparator pathogenic variant, affected or unaffected individual genotype, inheritance pattern, or cis/trans phase.
• The governing framework section states that no CDK4-specific CSPEC/VCEP framework was found; generic ACMG/AMP fallback therefore applies.

Still missing

• Inheritance mode and disease-specific allelic model for this case are not established.
• No pathogenic or likely pathogenic comparator variant is documented in the same individual.
• No parental, family, or molecular phasing establishes cis or trans configuration.

Sources

Reasoning

The evidence bundle does not document an affected patient with an alternative molecular diagnosis that explains the phenotype and thereby supports BP5. The presence of non-expert benign or likely benign ClinVar submissions is not BP5 evidence, and no patient-level alternative molecular basis is supplied.

Rule

Generic BP5 requires an alternative molecular explanation for the patient's phenotype; unrelated benign ClinVar assertions and absent patient-level diagnostic data are insufficient.

Still missing

• A documented alternative pathogenic molecular diagnosis in the affected patient, with phenotype attribution sufficient to exclude this variant as the cause, is unavailable.