PTCH1 c.2215_2216delinsTT, p.(His739Phe)

Reasoning

PM2 is met at supporting strength under the generic ACMG/AMP framework. The exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, the available reference population datasets reviewed for this case. No population frequency or homozygote observation was identified.

Rule

Generic ACMG/AMP PM2: apply at supporting strength when the variant is absent from or extremely rare in population databases appropriate for the disorder and ancestry context; the available case evidence supports absence from the reviewed datasets.

Evidence considered

• The exact normalized variant NM_000264.5:c.2215_2216delinsTT (PTCH1 p.His739Phe) was reported as absent from gnomAD v2.1.
• The exact normalized variant was reported as absent from gnomAD v4.1.
• The exact normalized variant was reported as absent from gnomAD-Canada v1.0.
• No allele frequency or homozygote count was available in the case bundle for the reviewed population resources.

Sources

Reasoning

SpliceAI predicts essentially no splicing impact for NM_000264.5:c.2215_2216delinsTT: all four delta scores are at or near zero (DS_AG=0.00, DS_AL=0.00, DS_DG=0.002, DS_DL=0.00; max delta = 0.002), well below the 0.1 'benign-supporting' cutoff derived from the SpliceAI calibration publication (Jaganathan et al., Cell 2019, PMID 30661751). This is the only calibrated computational predictor with usable output for this variant, since REVEL and BayesDel were both skipped (not SNV-compatible for this delins), and no gene-specific VCEP/CSPEC lookup overriding this was found. The splice-impact path therefore supports BP4 at supporting strength; this is not double-counted against PP3 (which is not_met) or BP7 (not applicable, this is a missense-changing variant, not synonymous).

Rule

SpliceAI max delta 0.002 < 0.1 (benign-supporting threshold) -> BP4 supporting via splice-impact path.

Evidence considered

• SpliceAI lookup for NM_000264.5:c.2215_2216delinsTT returned max delta score = 0.002 (DS_AG=0.00, DS_AL=0.00, DS_DG=0.002, DS_DL=0.00), well below the 0.1 threshold below which SpliceAI's original calibration study (Jaganathan et al., Cell 2019, PMID 30661751) indicates minimal likelihood of a splicing effect.
• REVEL and BayesDel were not computed for this variant (skipped as not-SNV), so no missense predictor evidence contributes to this BP4 call; the call rests solely on the SpliceAI splice-impact path.

Still missing

• No PTCH1-specific VCEP/CSPEC SpliceAI or missense-predictor threshold table was available to confirm or override the generic threshold used here.

Sources

Reasoning

This is a 2-bp delins (c.2215_2216delinsTT) producing a missense change (p.His739Phe). No governing VCEP/CSPEC was found for PTCH1 (framework_mode=generic_acmg, cspec.found=false), so generic thresholds apply. Splice-impact path: SpliceAI predicts no meaningful splice disruption (DS_AG=0.00, DS_AL=0.00, DS_DG=0.002, DS_DL=0.00; max delta = 0.002), far below the 0.2 'high recall' threshold from the original SpliceAI calibration publication (PMID 30661751), so SpliceAI does not support PP3. Missense in-silico path: REVEL and BayesDel scores were both explicitly not computed for this variant ('skipped: true, reason: not snv or no coords') because the tools require a simple SNV and this is a 2-bp delins, so no calibrated missense predictor evidence is available to invoke PP3 via that path either. No aGVGD or gene-specific PP3/BP4 lookup material was present in vcep_materials.json. Overall, no calibrated computational evidence supports a pathogenic prediction for this variant.

Rule

SpliceAI max delta 0.002 < 0.2 (no support for splice-altering effect); missense predictors (REVEL/BayesDel) not computable for this delins, so not invoked.

Evidence considered

• SpliceAI lookup for NM_000264.5:c.2215_2216delinsTT returned DS_AG=0.00, DS_AL=0.00, DS_DG=0.002, DS_DL=0.00 (max delta = 0.002), well below the 0.2 threshold identified as supporting a splicing effect in the original SpliceAI calibration study (Jaganathan et al., Cell 2019, PMID 30661751).
• REVEL and BayesDel scores were flagged in the case evidence bundle as skipped for this variant ('not snv or no coords'), so no calibrated missense predictor score is available for the p.His739Phe substitution.
• vcep_materials.json shows no CSPEC/VCEP was found for PTCH1 and no gene-specific PP3/BP4 lookup spreadsheet was provided, so no pre-assigned code applies.

Still missing

• REVEL and BayesDel could not be computed for this dinucleotide delins variant, so the missense in-silico path is uninformative rather than actively benign.
• No PTCH1-specific VCEP/CSPEC PP3/BP4 lookup table was available to check for a gene-specific override.

Sources

Reasoning

ClinVar contains an exact match for this variant, but the record has zero expert-panel submissions. The available assertions are ordinary single-submitter laboratory submissions, including Likely benign assertions, and the aggregate ClinVar record is not an expert-panel classification. Therefore PP5 is not met.

Rule

PP5 is applied only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary laboratory submissions, aggregate labels, and non-expert assertions are excluded.

Evidence considered

• ClinVar variation 219887 exactly matches NM_000264.5:c.2215_2216delinsTT (p.His739Phe), but the submission audit reports expert_panel_submissions: 0.
• The available ClinVar submissions are single-submitter laboratory assertions and include Likely benign or uncertain significance; ordinary submissions and aggregate labels do not trigger PP5.
• No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.

Sources

Reasoning

BA1 is not met. The exact variant was absent from the reviewed gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 datasets; therefore no population allele frequency exceeds the greater-than-1% benign threshold.

Rule

Generic ACMG/AMP BA1: apply when the allele frequency is greater than 1% in a population database; absence does not satisfy BA1.

Evidence considered

• The exact normalized variant NM_000264.5:c.2215_2216delinsTT (PTCH1 p.His739Phe) was reported as absent from gnomAD v2.1.
• The exact normalized variant was reported as absent from gnomAD v4.1 and gnomAD-Canada v1.0.
• Because the variant is absent rather than present above 1%, the BA1 frequency threshold is not reached.

Sources

Reasoning

BS1 is not met. No population allele frequency was observed for the exact variant in the reviewed gnomAD v2.1, gnomAD v4.1, or gnomAD-Canada v1.0 datasets, so the frequency is not greater than the expected disease prevalence threshold.

Rule

Generic ACMG/AMP BS1: apply when the observed allele frequency is greater than expected for the disorder; absence or an unobserved allele frequency does not satisfy BS1.

Evidence considered

• The exact variant was reported as absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
• No observed allele frequency is available from these population datasets that could exceed a disease-prevalence-based BS1 threshold.
• The case bundle does not provide a PTCH1-specific BS1 frequency cutoff or a quantitative prevalence/penetrance calculation; the observed absence nevertheless does not support BS1.

Sources

Reasoning

ClinVar contains an exact match, but there are zero expert-panel submissions. The Likely benign assertions are ordinary single-submitter laboratory submissions, and the aggregate ClinVar label is not an expert-panel assertion. Therefore BP6 is not met.

Rule

BP6 is applied only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary laboratory submissions, aggregate labels, and non-expert assertions are excluded.

Evidence considered

• ClinVar variation 219887 exactly matches NM_000264.5:c.2215_2216delinsTT (p.His739Phe), but the submission audit reports expert_panel_submissions: 0.
• The available Likely benign assertions are from ordinary clinical laboratory single-submitters and do not qualify for BP6 under the required expert-panel-only rule.
• No exact-variant ClinVar expert-panel Benign or Likely benign classification is present.

Sources

Reasoning

PS1 requires an established pathogenic/likely pathogenic variant that produces the identical amino acid change (p.His739Phe) via a different nucleotide substitution. No CSPEC/VCEP framework exists for PTCH1 (case_summary.compact_evidence.cspec.found=false; final_classification_framework.found=false), and no comparator variant search for the identical p.His739Phe substitution is present anywhere in the consolidated bundle. The only variant-level data available concerns this exact variant (NM_000264.5:c.2215_2216delinsTT, ClinVar VCV000219887, classified Likely benign/conflicting), which cannot be used as its own PS1 comparator.

Evidence considered

• case_summary.json cspec.found=false confirms no PTCH1 CSPEC/VCEP framework is available, so no PS1-specific rule modifications apply and generic ACMG PS1 semantics (same amino-acid change, different nucleotide change, established pathogenicity) would govern if a comparator existed.
• No same-amino-acid-change comparator variant (p.His739Phe caused by an alternate codon) was identified in ClinVar, PVS1 gene-context literature, or PM5 candidate collection materials included in this bundle.

Still missing

• No search for other pathogenic/likely pathogenic variants producing the identical p.His739Phe substitution was performed or returned in this case bundle.
• No ClinGen PTCH1 VCEP specification available to define PS1 thresholds/strength modifiers.

Reasoning

No proband-level de novo evidence is documented in the case-evidence bundle. There is no parental genotype information, confirmed maternity and paternity, or phenotype information for both biological parents. Therefore, a de novo occurrence cannot be established.

Rule

Generic ACMG/AMP PS2: apply only when the variant is confirmed de novo in the proband with confirmed maternity and paternity; do not apply without documented parental testing and appropriate phenotypic assessment.

Evidence considered

• The case-evidence bundle contains no documented proband/parent trio results, parental genotypes, or confirmed de novo observation for NM_000264.5:c.2215_2216delinsTT.
• The available case data identify the variant as PTCH1 NM_000264.5:c.2215_2216delinsTT (p.His739Phe), but do not provide the family testing details required for PS2.

Still missing

• Parental testing results for both biological parents are not provided.
• Maternity and paternity confirmation are not provided.
• Parental phenotypes and relevant age-related clinical assessment are not provided.

Reasoning

No validated functional assay evidence (minigene/complementation/reporter/enzymatic or other well-established functional study) for this specific variant, NM_000264.5:c.2215_2216delinsTT (p.His739Phe), was identified. PTCH1 has no ClinGen VCEP/CSPEC (framework_mode is generic_acmg, cspec.found=false), so no gene-specific PS3 assay-validation rubric applies. OncoKB explicitly reports no variant-specific reviewed functional evidence, only gene-level tumor-suppressor context. COSMIC and hotspot databases show no record of this variant. The only literature candidate flagged for PS3 (PMID:26467025) is a general DNA variant scoring/classification methodology paper and does not mention this variant or report any functional assay data for it; it was checked for text mentions of the variant/protein change and none were found. No other publication in the bundle reports a functional assay for this variant.

Evidence considered

• OncoKB evidence_sentence states no variant-specific reviewed functional evidence was identified for this variant; only gene-level curated context (PTCH1 as tumor suppressor/Hedgehog pathway inhibitor recurrently mutated in basal cell carcinoma) is available.
• PMID:26467025 (label: 'A Standardized DNA Variant Scoring System for Pathogenicity Assessments...') full text was checked for the variant identifiers c.2215_2216delinsTT, p.His739Phe, p.H739F, and delinsTT; none were found. This paper is a general scoring-system methodology publication, not a source of functional assay data for this variant.
• COSMIC and hotspot database queries both report the variant was not found/does not lie in a significant hotspot, consistent with absence of somatic/functional characterization data.

Still missing

• No functional assay (minigene, splicing reporter, complementation, biochemical) specific to c.2215_2216delinsTT (p.His739Phe) was located in the available literature packet or full-text set.
• No PTCH1 VCEP/CSPEC functional-evidence rubric is available to calibrate assay validity or strength even if such data existed.

Sources

Reasoning

No variant-specific affected-case series, case-control enrichment, or statistically supported excess of this exact PTCH1 variant in affected individuals is documented in the case-evidence bundle. The cited publications reviewed for this group did not provide an auditable exact-variant observation supporting PS4.

Rule

Generic ACMG/AMP PS4 requires a statistically significant increase in the prevalence of the variant in affected individuals compared with controls; insufficient exact-variant prevalence data means not assessed.

Evidence considered

• The case-evidence bundle contains no PS4 case-control data or verified variant-specific affected-case series.
• The reviewed literature records were not auditable exact-variant observations for NM_000264.5:c.2215_2216delinsTT and therefore were not used to infer PS4.

Still missing

• Variant-specific affected-case counts and an appropriate comparison cohort are unavailable.
• No case-control enrichment estimate or statistical significance is available for NM_000264.5:c.2215_2216delinsTT (p.His739Phe).

Sources

Reasoning

PM1 requires the variant to fall in a well-established mutational hotspot or critical/well-studied functional domain without benign variation. No CSPEC/VCEP PTCH1 domain framework is available in this case (vcep_materials.json shows no cspec url, files_found=[]), and no gene-specific functional/structural domain annotation for residue 739 of PTCH1 (e.g. sterol-sensing domain boundaries, extracellular loop annotation, or ClinVar-derived missense density map) is present in the bundle. The only hotspot check performed (cancerhotspots.org, a somatic cancer recurrence database) returned no result for PTCH1 H739, which is not equivalent to a germline ACMG PM1 domain/hotspot assessment and cannot substitute for one.

Evidence considered

• case_summary.json compact_evidence.hotspots.evidence_sentence states this variant does not lie in a statistically significant (somatic) hotspot per cancerhotspots.org, but this database queries recurrent somatic cancer mutations rather than germline structural/functional domain constraint, so it cannot be used to affirmatively apply or exclude PM1.
• No ClinGen PTCH1 VCEP specification or other domain-annotation source was found in vcep_materials.json to define PM1-qualifying regions of PTCH1.

Still missing

• No PTCH1 germline critical domain map or well-established mutational hotspot annotation was retrieved in this case bundle.
• cancerhotspots.org query is a somatic recurrence tool, not a validated PM1 germline domain source, and returned no_result; it is insufficient on its own to conclude absence or presence of a critical domain.

Reasoning

No applicable PTCH1-specific VCEP or gene framework was available, so generic ACMG/AMP was used. The case-evidence bundle contains no affected-proband observations, recessive inheritance context, second pathogenic or likely pathogenic allele, phase determination, or biallelic evidence for NM_000264.5:c.2215_2216delinsTT (p.His739Phe). PM3 therefore cannot be assessed.

Rule

Generic PM3 requires the variant to be observed in trans with a pathogenic or likely pathogenic variant in an affected individual with a recessive disorder, with strength determined by the applicable validated framework; no qualifying observation is available here.

Evidence considered

• The consolidated case-evidence bundle identifies PTCH1 and the variant as NM_000264.5:c.2215_2216delinsTT (p.His739Phe), but provides no affected-proband, biallelic, second-allele, or phase observations relevant to PM3.
• The bundle states that no official PTCH1 CSPEC/VCEP or local gene-specific framework was found; generic ACMG/AMP fallback is therefore applicable.
• ClinVar records and the listed literature are classification or general cohort sources without documented trans-phase or biallelic evidence for this variant in the supplied case bundle.

Still missing

• Affected-proband or affected-individual observations involving this variant are not documented.
• No second pathogenic or likely pathogenic variant is documented.
• No confirmed trans phase or other evidence of biallelic occurrence is documented.
• The applicable inheritance model for this specific observation is not provided.

Reasoning

PM5 requires a different pathogenic missense change previously established at the same residue (position 739). The dedicated pm5_candidates.json artifact in this case explicitly reports pm5_mode='unknown', eligible_for_classic_pm5_search=false, and zero candidates collected, with an explicit instruction that PM5 should not be applied from that artifact alone and that any same-residue comparator variants must be independently reviewed. No such comparator search or result is otherwise present in the consolidated bundle.

Evidence considered

• pm5_candidates.json (recommendation.level='not_applicable', recommendation.summary='Unable to confirm classic same-residue PM5 semantics safely; skipping automatic candidate harvesting') documents that the pipeline could not safely determine PM5 eligibility and explicitly instructs reviewers not to apply PM5 from that artifact alone; no comparator candidates (same_residue_candidates=0) were found.

Still missing

• pm5_candidates.json harvesting was explicitly skipped ('Unable to confirm classic same-residue PM5 semantics safely'); no automated or manual search for alternate pathogenic substitutions at codon 739 was completed in this case.
• No independent ClinVar or literature search for other His739 missense changes (e.g. p.His739Tyr, p.His739Arg) with established pathogenic/likely pathogenic classification is present in the bundle.

Sources

Reasoning

No suspected de novo occurrence is reported in the case-evidence bundle. Parental testing, maternity/paternity confirmation, and the clinical basis for suspecting a de novo event are absent, so PM6 cannot be applied.

Rule

Generic ACMG/AMP PM6: apply only for a suspected de novo occurrence without confirmation of maternity and paternity; the suspicion and supporting clinical/genetic observations must be documented.

Evidence considered

• The case-evidence bundle does not document an apparently de novo variant in a proband or any parental testing result for NM_000264.5:c.2215_2216delinsTT.
• No publication in the case bundle was specifically shown to report this exact variant with de novo evidence.

Still missing

• A reported de novo or apparently de novo observation in the proband is not provided.
• Parental genotype results are not provided.
• Maternity and paternity confirmation are not provided.
• Phenotypic information supporting a de novo disease presentation is not provided.

Reasoning

No affected or unaffected relatives, informative meioses, segregation observations, or family phenotype/genotype data are documented. Consequently, there is no evidence from which to assess cosegregation of the variant with disease.

Rule

Generic ACMG/AMP PP1: apply when a variant is shown to cosegregate with disease in multiple affected family members, with strength calibrated to the number of informative meioses and the quality of phenotype assignment; no strength is assigned without segregation data.

Evidence considered

• The case-evidence bundle contains no family pedigree, relative testing results, segregation table, or informative-meiosis count for NM_000264.5:c.2215_2216delinsTT.
• The available ClinVar and population/database entries do not provide family segregation evidence and cannot substitute for documented cosegregation data.

Still missing

• Number and identities of tested affected relatives are not provided.
• Number and identities of tested unaffected relatives are not provided.
• Genotypes and phenotypes for relatives are not provided.
• Informative meioses and segregation count are not provided.
• Phenotype definition and consistency with the PTCH1-associated disorder are not provided.

Reasoning

PP2 requires a missense variant in a gene for which missense variants are a common mechanism of disease and benign missense variation is uncommon. No CSPEC/VCEP PTCH1 framework or missense constraint metrics (e.g. gene-level missense Z-score, ClinVar benign-missense proportion) are present anywhere in this bundle. The available PTCH1 gene mechanism context (pvs1_gene_context.json) documents loss-of-function as the supported germline disease mechanism for Gorlin syndrome (splice-site, frameshift, nonsense variants featured in supporting literature), but this does not by itself establish or refute whether missense substitution is also a common disease mechanism for PTCH1, which is what PP2 formally requires.

Evidence considered

• pvs1_gene_context.json documents lof_mechanism_supported=true for PTCH1 germline Gorlin syndrome, based on literature emphasizing splice-site and frameshift pathogenic variants, but does not provide missense-specific constraint data needed to affirmatively apply PP2.

Still missing

• No missense constraint metric (missense Z-score, o/e ratio, or benign-missense rate) for PTCH1 is present in this bundle.
• No CSPEC/VCEP PTCH1 statement on whether missense is a common disease mechanism was available (vcep_materials.json files_found=[]).

Sources

Reasoning

The bundle provides no patient phenotype, clinical diagnostic criteria, or phenotype-to-disease specificity assessment for the individual carrying this exact variant. Gene-level descriptions of Gorlin syndrome are insufficient to apply PP4 to this case.

Rule

Generic ACMG/AMP PP4 may be applied only when the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; patient-specific phenotype data are unavailable.

Evidence considered

• The case summary identifies PTCH1 and the variant but does not provide an individual-level phenotype or diagnostic feature set.
• General syndrome descriptions in the reviewed publications were not treated as patient-specific PP4 evidence.

Still missing

• Patient-level phenotype and clinical diagnostic information are missing.
• No assessment establishes that the patient's phenotype is highly specific for PTCH1-related Gorlin syndrome.

Sources

Reasoning

BS2 cannot be assessed from the available evidence. The population resources report the exact variant as absent, but the bundle provides no documented healthy adult homozygotes, hemizygotes, or unaffected individuals with a genotype that would support BS2.

Rule

Generic ACMG/AMP BS2: apply when the variant is observed in healthy adults in a genotype inconsistent with a highly penetrant disorder, such as homozygotes or hemizygotes; absence alone is insufficient.

Evidence considered

• The reviewed population datasets report the exact variant as absent; absence is not evidence of healthy homozygous or hemizygous individuals.
• The case bundle contains no qualifying healthy-individual genotype observations for this variant.

Still missing

• No documented healthy adult homozygotes or hemizygotes were identified.
• No unaffected carrier genotype observations or phenotype-follow-up data were provided for this exact variant.

Sources

Reasoning

No functional assay evidence of any kind (showing normal/wild-type-like activity or no damaging effect) for NM_000264.5:c.2215_2216delinsTT (p.His739Phe) was identified in the available literature packet, full-text papers, OncoKB, or COSMIC/hotspot data. PTCH1 has no ClinGen VCEP/CSPEC to define a BS3 assay rubric (framework_mode is generic_acmg). Absent any assay data, BS3 cannot be assessed either as met or not_met.

Evidence considered

• OncoKB evidence_sentence states no variant-specific reviewed functional evidence was identified for this variant.

Still missing

• No functional assay data of any polarity (damaging or benign) specific to this variant was located.
• No PTCH1 VCEP/CSPEC functional-evidence rubric is available to calibrate assay validity or strength even if such data existed.

Sources

Reasoning

No unaffected relatives who were tested for the variant are described. Therefore, non-segregation cannot be evaluated and BS4 cannot be applied.

Rule

Generic ACMG/AMP BS4: apply when a variant is observed in unaffected individuals with the disease, with appropriate consideration of age, penetrance, and phenotype ascertainment; no strength is assigned without documented non-segregation.

Evidence considered

• The case-evidence bundle contains no documented unaffected relatives carrying NM_000264.5:c.2215_2216delinsTT and no non-segregation analysis.
• Absence of family data is insufficient to establish BS4; no source in the bundle provides the required affected/unaffected relative comparison.

Still missing

• Tested unaffected relatives are not identified.
• Genotypes and clinical phenotypes of potentially informative unaffected relatives are not provided.
• Age, surveillance status, and phenotype penetrance considerations for unaffected carriers are not provided.

Reasoning

BP1 requires evidence that missense variants are not a common mechanism of disease for the gene. No missense constraint metrics or CSPEC/VCEP PTCH1 statement addressing whether missense is a common vs. uncommon disease mechanism are present in this bundle. While pvs1_gene_context.json supports a loss-of-function germline disease mechanism for PTCH1 (Gorlin syndrome), this literature context focuses on truncating/splice variants and does not provide the quantitative missense-rate data (e.g., proportion of pathogenic ClinVar missense variants, benign missense enrichment) needed to affirmatively apply BP1.

Evidence considered

• pvs1_gene_context.json documents lof_mechanism_supported=true for PTCH1, indicating the literature emphasis on loss-of-function (splice/frameshift/nonsense) as the germline Gorlin syndrome mechanism, but this alone is insufficient to formally apply BP1 without quantitative missense-rate/constraint data.

Still missing

• No missense constraint metric or systematic review of PTCH1 missense variant pathogenicity proportions is present in this bundle to support or refute BP1.
• No CSPEC/VCEP PTCH1 gene-mechanism statement was available (vcep_materials.json files_found=[]).

Sources

Reasoning

No applicable PTCH1-specific VCEP or gene framework was available, so generic ACMG/AMP was used. The case-evidence bundle contains no documented observation of this variant in trans with a pathogenic variant for a dominant disorder, nor in cis with a pathogenic variant for a recessive disorder. BP2 therefore cannot be assessed.

Rule

Generic BP2 requires observation in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant for a recessive disorder; no qualifying phase observation is available here.

Evidence considered

• The consolidated case-evidence bundle contains no phase information, family segregation data, or linked pathogenic-variant observation for NM_000264.5:c.2215_2216delinsTT (p.His739Phe).
• The bundle states that no official PTCH1 CSPEC/VCEP or local gene-specific framework was found; generic ACMG/AMP fallback is therefore applicable.
• The supplied ClinVar and literature materials do not document a BP2-qualifying cis or trans relationship for this variant.

Still missing

• No family or individual-level data establish phase with another pathogenic variant.
• No pathogenic variant in trans or cis is identified in the supplied evidence.
• No inheritance-model and phenotype context is supplied for a BP2-qualifying observation.

Reasoning

No patient-level evidence shows that the individual's phenotype is explained by a pathogenic variant in another gene or by another established molecular cause. The existence of non-expert Likely benign ClinVar submissions is not BP5 evidence.

Rule

Generic ACMG/AMP BP5 requires a pathogenic variant in an alternative gene that explains the patient's phenotype; no such case-level evidence is available.

Evidence considered

• The case-evidence bundle contains no alternative molecular diagnosis for an affected individual.
• ClinVar's ordinary laboratory assertions were not used as BP5 evidence because BP5 concerns an alternative molecular explanation in the case, not a submission label for the queried variant.

Still missing

• Patient-level phenotype and molecular testing for an alternative genetic cause are unavailable.
• No documented alternative pathogenic variant explains the relevant phenotype.