CDKN2A c.341C>T, p.(Pro114Leu)

Reasoning

No CDKN2A VCEP specification is available for this case (cspec.found=false, framework_mode=generic_acmg), so generic ACMG/AMP PS3 criteria were applied. Miller et al. 2011 (PMID:21462282) is a CDKN2A-specific functional/computational compilation study using a validated flow-cytometry G0/G1 cell-cycle arrest assay in U2OS cells with appropriate controls (vector-only negative control, nonfunctional 2-bp-deletion mutant, and wild-type positive control; Figure 1), each variant tested in >=3 independent replicate experiments, with an explicit reliability threshold (>=15% difference in arrest vs wild-type/vector needed for a reliable call). p.P114L is shown in Figure 3B as a familial-melanoma-associated (red bar) variant clustering with clear loss-of-function variants (near L97R, at the low end of the % relative arrest ranking), and the paper states results for p.P114L were confirmed/previously reported (Greenblatt et al. 2003) and included in this cohort's meta-analysis. p.P114L is also listed in Table 2 in the 'Cdk4 loss/Cdk6 normal' impaired-binding category (FM-associated), providing a second, independent biochemical assay (CDK4 binding) concordant with loss of cell-cycle inhibitory function -- consistent with the known CDKN2A tumor-suppressor mechanism (CDK4/6-cyclin D-Rb pathway inhibition). The authors calculated the PPV of a single loss-of-function cell-cycle assay result in this cohort to be ~100% (31/31 damaging-by-assay variants confirmed pathogenic by clinical or other-assay data, no false positives), and assigned this assay an odds ratio of 19 for pathogenicity in their own Bayesian integration, ultimately classifying p.P114L as Class 5 (pathogenic) using >=2 independent functional/hotspot data types. Given the validated, controlled, replicated, concordant multi-assay evidence directly probing the CDKN2A tumor-suppressor mechanism, PS3 is met at Strong. Flagged for human review because the original primary assay data point for p.P114L traces to an earlier publication (Greenblatt et al. 2003) that is not present in this case's source bundle or full-text set -- only the confirmatory compilation/re-reporting in PMID:21462282 was directly reviewed.

Rule

PS3_generic_ACMG_2015

Evidence considered

• PMID:21462282 Figure 1: flow-cytometry G0/G1 cell-cycle arrest assay methodology in U2OS cells with vector-only negative control, nonfunctional 2-bp-deletion control, and wild-type positive control.
• PMID:21462282 Figure 3B: p.P114L shown as a familial-melanoma-associated (red) variant with markedly reduced G0/G1 arrest relative to wild-type, grouped among clear loss-of-function variants; results 'previously reported [Greenblatt et al., 2003]' and re-confirmed in this cohort.
• PMID:21462282 Table 2: p.P114L listed under 'Cdk4 loss/Cdk6 normal' impaired-binding category, FM-associated -- a second, independent biochemical assay concordant with loss of function.
• PMID:21462282 main text: 'PPV (correct prediction of pathogenic based on in vitro results) was excellent for both cell cycle and binding assays... no cases did clinical or other laboratory studies suggest a neutral variant (PPV 100%).'
• PMID:21462282 main text: p.P114L classified as Class 5 (pathogenic) by the paper's integrated Bayesian analysis using >=2 independent data types (functional assay + somatic hotspot status), assigned an in vitro assay OR of 19 for pathogenicity.

Still missing

• The primary source publication for the original p.P114L cell-cycle arrest data point (Greenblatt et al. 2003, cited within PMID:21462282) is not present in this case's source_registry or publications folder and could not be independently reviewed for assay-specific controls/statistics.
• PMID:8755727 and PMID:7777061 (in vitro p16 functional/cdk4-inhibition studies present in source_registry) could not be confirmed as testing the specific P114L variant -- only abstract snippets were available and neither explicitly names p.P114L -- so they were not used as PS3 support.

Sources

Reasoning

p.Pro114Leu falls within the ankyrin-repeat region of p16INK4A (encoded by CDKN2A transcript captured here as NM_001195132.1/NP_001182061.1, equivalent to NM_000077.5 p.Pro114Leu), the domain structurally required for CDK4/CDK6 binding and inhibitory function. Cancerhotspots.org flags codon P114 as a statistically significant mutational hotspot, and COSMIC records 92 independent somatic occurrences at this variant (COSV58683051), with OncoKB annotating the variant as curated 'Oncogenic' with a loss-of-function biological effect. A separate CDKN2A missense variant located in the functionally critical first ankyrin repeat (p.Gly23Ser) has independently been established as pathogenic on the basis of that domain's functional importance, supporting that ankyrin-repeat missense substitutions in this gene are recurrently deleterious. Together these indicate codon 114 lies in a well-characterized functional domain/mutational hotspot without established benign missense variation, supporting PM1 at moderate strength. Confidence is tempered because the hotspot extraction itself carries a flagged parsing caveat.

Rule

Generic ACMG/AMP (Richards et al. 2015, PMID:25741868) PM1 - located in a mutational hot spot and/or critical and well-established functional domain without benign variation; no CDKN2A-specific VCEP CSPEC was retrieved for this case (cspec.found=false).

Evidence considered

• Cancerhotspots.org (queried as 'CDKN2A P114') returned 'This variant lies in a statistically significant hotspot,' though the row extraction was only partially parsed and the tool flagged 'Regex extraction partial; verify screenshot.'
• COSMIC (COSV58683051) reports this exact variant recurrent in somatic cancers 92 times.
• OncoKB curates p.P114L as 'Oncogenic' with biological effect 'Loss-of-function', citing PMID:7777061 and PMID:8755727 as its supporting functional literature.
• PMID:17992122 (Gensini et al. 2007) independently establishes that a different CDKN2A ankyrin-repeat missense change, p.Gly23Ser, is pathogenic in part because it lies 'in the functionally important first ankyrinic domain of p16,' supporting that ankyrin-repeat missense substitutions in this gene are a recognized mechanism of pathogenicity for the domain that also contains residue 114.
• gnomAD shows the variant absent/not observed in both v2.1 (0/239394 alleles) and v4.1 exomes, consistent with strong negative selection against substitutions in this region, though this fact alone supports PM2 rather than PM1 and is cited here only as corroborating context for domain intolerance.

Still missing

• The cancerhotspots.org 'hotspots' evidence record carries a warning ('Regex extraction partial; verify screenshot'), so the underlying hotspot statistic (p-value/mutation count at P114 specifically) could not be independently confirmed from structured data alone; screenshot/manual verification is recommended.
• COSMIC and cancerhotspots.org reflect somatic tumor recurrence rather than a germline-specific domain/hotspot analysis; no CDKN2A VCEP CSPEC was available to confirm whether these somatic-derived hotspot data are an accepted PM1 basis for germline classification of this gene.

Sources

Reasoning

PM2 is met at the generic ACMG/AMP moderate strength: CDKN2A p.(Pro114Leu) is absent from gnomAD v4.1 and gnomAD-Canada v1.0 and has AC=0/AN=239394 (AF=0) in gnomAD v2.1, including zero alleles in every reported ancestry group. The result is not an artifact of a single database or ancestry-specific frequency signal.

Rule

Generic ACMG/AMP 2015 fallback: PM2 (moderate) applies when a variant is absent from controls (or at extremely low frequency if recessive).

Evidence considered

• gnomAD v2.1 reports AC=0/AN=239394 (AF=0) and 0 homozygotes; the largest reported ancestry stratum, African/African American, is AC=0/AN=15238.
• The variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0, corroborating absence across independently queried population resources.
• No CDKN2A VCEP or gene-specific PM2 specification was retrieved, so the generic ACMG/AMP 2015 PM2 strength is used.

Sources

Reasoning

CDKN2A/p16INK4A is a tumor-suppressor gene in which missense substitutions within the ankyrin-repeat CDK4/6-binding domain are a recognized and recurrent disease mechanism, distinct from a gene where disease is driven primarily by truncating variants. Multiple ClinVar submitters have classified this same missense variant (p.Pro114Leu) as Likely pathogenic or Pathogenic on the basis of computational/laboratory functional assessment, and functional literature specifically developed a framework for classifying CDKN2A missense variants using computational and laboratory studies, reflecting that missense variation is an established, non-rare mechanism of pathogenicity in this gene (contrasted with a gene dominated by loss-of-function/truncating variants). This supports PP2 at supporting strength under the generic ACMG framework.

Rule

Generic ACMG/AMP (Richards et al. 2015, PMID:25741868) PP2 - missense variant in a gene for which missense variants are a common mechanism of disease; no CDKN2A-specific VCEP CSPEC was retrieved for this case (cspec.found=false).

Evidence considered

• ClinVar record for this exact variant (VCV000077637) shows independent classifications of Likely pathogenic and Pathogenic from separate laboratories based on missense change p.Pro114Leu, indicating missense variation at this locus is treated as a disease-causing mechanism rather than incidental.
• PMID:21462282 (Miller et al. 2011), 'Classifying variants of CDKN2A using computational and laboratory studies,' establishes a dedicated framework for interpreting CDKN2A missense variants, reflecting that missense substitution is a recognized, common mechanism of CDKN2A pathogenicity requiring systematic functional/computational classification.
• PMID:17992122 documents an independent pathogenic CDKN2A missense variant (p.Gly23Ser) acting through disruption of the ankyrin-repeat domain, corroborating that missense substitution (not only truncation) is an established disease mechanism for this gene.

Still missing

• No formal CDKN2A missense-variant benign/pathogenic ratio or ClinGen missense constraint (Z-score/o:e ratio) metric was present in the evidence bundle to numerically confirm 'benign missense variation is uncommon' beyond the qualitative literature/ClinVar pattern cited.

Sources

Reasoning

No CDKN2A-specific VCEP CSPEC or gene-specific PP3/BP4 lookup table is present in this case bundle (case_summary.cspec.found=false; vcep_materials.found=false; framework_mode=generic_acmg), so generic ACMG/AMP computational evidence rules apply. NM_001195132.1:c.341C>T is a missense variant (NP_001182061.1:p.(Pro114Leu)). Local REVEL lookup returns a score of 0.872 for this variant. Using the ClinGen SVI-recommended REVEL calibration thresholds published in Pejaver et al. 2022 (PMID 36413997), REVEL >=0.773 meets the pathogenic-moderate threshold (strong requires >=0.932), so PP3 is met at Moderate strength via the missense in-silico path. SpliceAI predicts no splice impact for this exonic missense substitution (max delta score = 0.00), which is expected/uninformative for a variant away from splice consensus sequence and is not used to support PP3 (no double counting across the splice-impact and missense in-silico paths). BayesDel score (0.521199) is available in prefetch data but is not used to support or corroborate this call because no verified published BayesDel threshold/publication is available to this pipeline.

Rule

generic_acmg_pp3_missense_revel_calibrated

Evidence considered

• REVEL score = 0.872 for NM_001195132.1:c.341C>T (NP_001182061.1:p.(Pro114Leu)), from local REVEL v1.3 lookup (source_registry key 'revel').
• ClinGen SVI-recommended REVEL calibration (Pejaver V et al., PMID 36413997, Am J Hum Genet 2022): REVEL >=0.773 corresponds to PP3_Moderate; 0.872 falls in the Moderate band (below the >=0.932 Strong threshold).
• SpliceAI max delta score = 0.00 (source_registry key 'spliceai') indicates no predicted splicing disruption; not used to support PP3 since PP3 here is being applied via the missense in-silico path, avoiding double counting.

Sources

Reasoning

ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion. The available Pathogenic/Likely pathogenic assertions are ordinary laboratory submissions and cannot trigger PP5.

Rule

Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• The exact ClinVar record for p.Pro114Leu has four submissions and zero expert-panel submissions; its Pathogenic and Likely pathogenic submissions are single-submitter laboratory assertions.

Sources

Reasoning

BA1 is not met: the variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0 and has AC=0/AN=239394 (AF=0) in gnomAD v2.1; therefore, it does not meet the generic ACMG/AMP stand-alone benign high-frequency criterion.

Rule

Generic ACMG/AMP 2015 fallback: BA1 requires an allele frequency greater than 5% in a population database.

Evidence considered

• gnomAD v2.1 reports 0 alternate alleles among 239394 alleles (AF=0), with 0 homozygotes; its largest ancestry stratum, African/African American, is also AC=0/AN=15238.
• The variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0.

Sources

Reasoning

BS1 is not met: no alternate alleles are observed in gnomAD v2.1 and the variant is absent from gnomAD v4.1 and gnomAD-Canada v1.0, so its frequency cannot be greater than that expected for a CDKN2A-associated dominant cancer-predisposition disorder.

Rule

Generic ACMG/AMP 2015 fallback: BS1 applies only when allele frequency is greater than expected for the disorder; no CDKN2A-specific frequency threshold was retrieved.

Evidence considered

• gnomAD v2.1 reports AC=0/AN=239394, AF=0, and no homozygotes; no ancestry group has an observed alternate allele.
• The independent gnomAD v4.1 and gnomAD-Canada v1.0 lookups both report the variant absent.

Sources

Reasoning

The only variant-specific functional data identified (PMID:21462282, validated G0/G1 cell-cycle arrest assay with controls, plus concordant CDK4-binding assay) shows p.P114L has a damaging/loss-of-function effect, not a wild-type/benign result. No source in this case's evidence bundle reports a wild-type or benign functional assay result for p.P114L. BS3 is therefore not met; this is the expected inverse outcome given PS3 is met on the same evidence.

Rule

BS3_generic_ACMG_2015

Evidence considered

• PMID:21462282 Figure 3B and Table 2 both show p.P114L with impaired (not wild-type) function in cell-cycle arrest and CDK4 binding assays, precluding a BS3 (benign functional) call.

Sources

Reasoning

BP1 applies to missense variants in genes where disease is caused primarily by truncating/loss-of-function variants rather than missense substitution. As established for PP2 above, CDKN2A/p16INK4A has a well-documented missense pathogenic mechanism (ankyrin-repeat domain disruption impairing CDK4/6 inhibition), so BP1's premise (missense variation is not an expected disease mechanism) does not hold for this gene, and BP1 is not met.

Rule

Generic ACMG/AMP (Richards et al. 2015, PMID:25741868) BP1 - missense variant in a gene for which primarily truncating variants cause disease; not applicable here since CDKN2A missense variation is an established mechanism (see PP2).

Evidence considered

• Same evidence supporting PP2 (recurrent missense pathogenic classifications in ClinVar for this and other CDKN2A residues, and literature establishing missense-driven ankyrin-domain disruption as a disease mechanism) demonstrates missense variation is a recognized, not incidental, mechanism for this gene, so the BP1 premise is not satisfied.

Sources

Reasoning

No CDKN2A-specific VCEP CSPEC or gene-specific lookup table pre-assigns BP4 for this variant. On the missense in-silico path, REVEL = 0.872 falls well above the ClinGen SVI-recommended (Pejaver et al. 2022, PMID 36413997) benign thresholds (BP4_supporting requires REVEL <=0.183), so the calibrated missense predictor evidence argues against, not for, a benign computational call. On the splice-impact path, SpliceAI predicts max delta score = 0.00 for this variant, i.e. no splicing disruption predicted; however this is expected for an exonic missense substitution not located at a splice consensus site, and low SpliceAI scores alone are not being used here to assert a benign splicing conclusion because the variant's dominant mechanism under evaluation is missense substitution (already addressed, in the opposite direction, by REVEL under PP3). BayesDel score (0.521199) is present but not usable for BP4 because no verified published BayesDel threshold/publication is available to this pipeline; it is therefore treated as not_available and not weighed in either direction, per project policy. BP7 is not applicable because this is a missense variant, not synonymous.

Rule

generic_acmg_bp4_missense_revel_calibrated

Evidence considered

• REVEL score = 0.872 (source_registry key 'revel') exceeds the ClinGen SVI (Pejaver et al., PMID 36413997) benign-supporting threshold of <=0.183, so REVEL does not support BP4.
• SpliceAI max delta score = 0.00 (source_registry key 'spliceai') shows no predicted splice disruption, but is not treated as independent BP4-supporting evidence for this missense variant to avoid double counting against the REVEL-based missense assessment.
• BayesDel score = 0.521199 is available (source_registry key 'bayesdel') but has no verified published calibration/threshold accessible to this pipeline, so it is treated as not_available for BP4 per project policy rather than being interpreted using any recalled cutoff.

Sources

Reasoning

ClinVar has no exact-variant expert-panel Benign or Likely benign assertion. No ClinVar submission for this exact variant is Benign or Likely benign, and ordinary laboratory assertions would not trigger BP6 in any event.

Rule

Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• The exact ClinVar record for p.Pro114Leu has zero expert-panel submissions and contains Likely pathogenic, Pathogenic, and Uncertain significance assertions only.

Sources

Reasoning

PS1 requires a distinct nucleotide change at the same codon that is predicted to produce the identical amino acid change (p.Pro114Leu) and that has itself been established as pathogenic. No CDKN2A-specific VCEP CSPEC exists for this variant (cspec.found=false), so the generic ACMG framework applies, but no such alternate-codon/same-amino-acid-change search was performed or returned in this case's evidence bundle (prefetch, evidence, ClinVar record, or pm5_candidates.json all address only the observed c.341C>T allele; pm5_candidates.json explicitly did not run a same-residue comparator harvest). Without a confirmed second nucleotide variant encoding the same p.Pro114Leu change with an established pathogenic classification, PS1 cannot be applied.

Still missing

• No dedicated search for alternate codon 341-region nucleotide substitutions that would also yield p.Pro114Leu was captured in the evidence bundle; a manual ClinVar/literature search restricted to NM_001195132.1/NM_000077.5 c.341 position variants encoding p.Pro114Leu is needed to assess PS1.

Reasoning

No de novo observation is documented. The case bundle contains no proband-parent trio result, parental genotype, parentage confirmation, or phenotype information for tested parents.

Rule

Generic ACMG/AMP PS2 requires a confirmed de novo variant in an affected individual with no family history; no gene-specific CDKN2A specification was available.

Evidence considered

• ClinVar records germline clinical submissions for the exact variant but the supplied record does not provide parental genotypes, parentage confirmation, or a de novo assertion.

Still missing

• Obtain the proband genotype and parental testing results for c.341C>T (p.Pro114Leu).
• If both parents are negative, document biological parentage confirmation, parental phenotypes, and the proband phenotype before reassessing de novo evidence.

Sources

Reasoning

No case-control enrichment data were identified. The directly reviewed CDKN2A study records p.Pro114Leu in one familial-melanoma family, which is not a case-control comparison and is insufficient to establish increased prevalence in affected individuals versus controls.

Rule

Generic ACMG/AMP PS4: prevalence in affected individuals must be significantly increased compared with controls.

Evidence considered

• No applicable CDKN2A CSPEC/VCEP specification was retrieved; generic ACMG/AMP PS4 was used.
• PMID:21462282, Table 1C, lists p.P114L with one familial-melanoma family and one total carrier; it does not provide matched control counts or a case-control effect estimate.

Still missing

• A phenotype-defined case-control study reporting p.Pro114Leu carrier counts in affected individuals and ancestry-matched controls, with an effect estimate and confidence interval.

Sources

Reasoning

PM5 requires a different missense change at the same residue (Pro114) previously established as pathogenic. The case's dedicated PM5 comparator pipeline (pm5_candidates.json) explicitly declined to harvest candidates, stating: 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting,' with zero candidates returned (same_residue_candidates=0) and an explicit recommendation to not apply PM5 from that artifact alone. No other source in the evidence bundle identifies an alternate amino-acid substitution at codon 114 with an established pathogenic classification, so PM5 cannot be assessed as met or not_met from the available evidence.

Evidence considered

• pm5_candidates.json (PM5 comparator candidate collection) reports found=false, eligible_for_classic_pm5_search=false, and zero same_residue_candidates, with the stated reason: 'Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting.'

Still missing

• A manual/targeted ClinVar and literature search for other CDKN2A missense variants at codon 114 (e.g., p.Pro114Ser, p.Pro114His, p.Pro114Arg, etc.) with an established pathogenic classification is needed to determine PM5 eligibility; pm5_candidates.json intentionally returned no candidates and flagged the semantics as unresolved.

Sources

Reasoning

No assumed de novo observation is documented. The bundle provides no parental testing result from which absence in parents could be established without parentage confirmation.

Rule

Generic ACMG/AMP PM6 requires an assumed de novo variant without confirmation of paternity and maternity; no gene-specific CDKN2A specification was available.

Evidence considered

• The exact-variant ClinVar record includes germline submissions but no reported parental test result or assumed de novo observation.

Still missing

• Obtain parental genotypes for c.341C>T (p.Pro114Leu).
• Document the proband phenotype and whether biological parentage was confirmed.

Sources

Reasoning

No qualifying co-segregation data are available. The reviewed full-text report lists p.Pro114Leu in one familial-melanoma family but tabulates only one carrier and provides no informative affected/unaffected relative genotypes or meiosis count.

Rule

Generic ACMG/AMP PP1 requires co-segregation with disease in multiple affected family members; no gene-specific CDKN2A specification was available.

Evidence considered

• Miller et al. classify FM-associated variants as those found in probands from multiple familial-melanoma families or multiple affected individuals in one family, but their Table 1C lists p.Pro114Leu in one FM family with one total carrier; this is not a reported co-segregation analysis.

Still missing

• Obtain a pedigree with melanoma and other relevant cancer phenotypes, ages, and genotype results for informative relatives.
• Provide the number of informative meioses and account for age-dependent/incomplete penetrance before reassessing segregation.

Sources

Reasoning

The case bundle contains no individual-level phenotype, family history, tumor phenotype, or diagnostic work-up for the tested person. Therefore phenotype specificity for a CDKN2A-associated condition cannot be evaluated.

Rule

Generic ACMG/AMP PP4: the patient's phenotype or family history must be highly specific for a disease with a single genetic etiology.

Evidence considered

• No applicable CDKN2A CSPEC/VCEP specification was retrieved; generic ACMG/AMP PP4 was used.
• The bundle provides variant-level resources and ClinVar condition labels but no phenotype for the individual being assessed.

Still missing

• Individual-level phenotype and family-history data, including melanoma and pancreatic-cancer history, age at onset, multiple-primary-melanoma status, and relevant differential diagnoses.

Reasoning

BS2 cannot be assessed from the available population data. The variant is absent rather than observed in unaffected adult individuals; moreover, CDKN2A-associated cancer predisposition has age-dependent and incomplete penetrance, so a homozygote count of zero supplies no BS2 evidence.

Rule

Generic ACMG/AMP 2015 fallback: BS2 requires observation in a healthy adult individual for a disorder expected to be fully penetrant at an early age; that condition is not established here.

Evidence considered

• gnomAD v2.1 reports AC=0/AN=239394 and 0 homozygotes; gnomAD v4.1 and gnomAD-Canada v1.0 report the variant absent.
• Population-database absence and zero homozygotes cannot establish observation in healthy adults.

Still missing

• No well-phenotyped cohort data identifying unaffected older adult carriers, with age and cancer-status information sufficient to evaluate penetrance, were provided.

Sources

Reasoning

No well-documented non-segregation evidence is available. The reviewed report does not describe an affected relative lacking p.Pro114Leu or a genotype-phenotype discordance that could establish lack of segregation.

Rule

Generic ACMG/AMP BS4 requires lack of segregation in affected members; no gene-specific CDKN2A specification was available.

Evidence considered

• Miller et al. list p.Pro114Leu in one familial-melanoma family with one total carrier and do not report genotype-negative affected relatives or other variant-specific non-segregation evidence.

Still missing

• Obtain genotype and phenotype data for affected and unaffected relatives, with ages and ascertainment details.
• Establish whether any affected relative lacks c.341C>T (p.Pro114Leu) while accounting for phenocopies and age-dependent/incomplete penetrance.

Sources

Reasoning

No qualifying allelic observation is available. The bundle contains no report of c.341C>T (p.Pro114Leu) occurring in cis with a pathogenic/likely pathogenic CDKN2A variant, nor a phase-confirmed trans occurrence with such a variant in an appropriate affected or unaffected individual. BP2 cannot be applied from the reported ClinVar classifications or from variant-level case observations alone.

Rule

Generic ACMG/AMP BP2: consider only when the variant is observed in cis with a pathogenic variant, or in trans with a pathogenic variant for a fully penetrant dominant disorder; phase and clinical context must be established.

Evidence considered

• No CDKN2A CSPEC/VCEP framework was retrieved; the case is governed by the generic ACMG/AMP fallback.
• The case bundle includes germline ClinVar submissions for c.341C>T but supplies no co-occurring CDKN2A variant, cis/trans phase, parental segregation, or unaffected-carrier observation that would satisfy BP2.

Still missing

• A documented co-occurring pathogenic/likely pathogenic CDKN2A variant is needed.
• Molecular phasing (cis or trans), preferably supported by parental testing or read-backed phase, is needed.
• For a trans-based BP2 consideration, the individual's phenotype and the penetrance/clinical relevance of the dominant CDKN2A condition must be documented.

Reasoning

No individual-level phenotype or molecular diagnostic findings are provided, so there is no evidence to determine whether an alternate molecular cause fully explains the presentation.

Rule

Generic ACMG/AMP BP5: a variant is found in a case with an alternate molecular basis for disease.

Evidence considered

• No applicable CDKN2A CSPEC/VCEP specification was retrieved; generic ACMG/AMP BP5 was used.
• The bundle does not contain an individual-level alternate molecular diagnosis.

Still missing

• The individual's clinical phenotype and molecular testing results, including any pathogenic or likely pathogenic variant that could independently explain the presentation.