{ "schema_version": "1.0", "purpose": "Publisher-authored task examples with observed public tool responses; not an independent evaluation or a frozen benchmark. Query again for current evidence.", "examples": [ { "case_id": "refseq-brca1-deletion", "input": "NM_007294.4:c.68_69del", "status": "resolved", "identity": { "alternate": "A", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43124027:ACT:A", "chromosome": "chr17", "position": 43124027, "reference": "ACT", "variant_type": "DEL" }, "automated_class": "P", "criteria": "PVS1,PS1,BS1_Strong[VCEP][af_grpmax] [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]", "classifier_version": "3.39.1", "evidence_availability": { "clinvar": "available", "conservation": "no_record", "dosage": "available", "expert": "available", "gene_constraints": "available", "population": "available", "predictors": "no_record", "spliceai": "no_record" }, "observed_at_utc": "2026-09-10T16:37:12Z", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": "2026-01" }, { "name": "clinvar", "version": "2026-01" }, { "name": "dbnsfp", "version": "4.9c" }, { "name": "ensembl_vep", "version": "Release 113" }, { "name": "erepo_classifications", "version": "erepo-2026-06-04" }, { "name": "exon_pext", "version": "2.1.1" }, { "name": "g2p", "version": "2026-01" }, { "name": "gnomad", "version": "4.1" }, { "name": "gnomad_constraint", "version": "4.1" }, { "name": "gof_genes", "version": "2026-01" }, { "name": "hpo", "version": "2026-01" }, { "name": "interpro_pfam", "version": "2026-03" }, { "name": "mane_select", "version": "2.0" }, { "name": "mt_apogee2_scores", "version": "APOGEE2 v2.0" }, { "name": "mt_clinvar_variants", "version": "ClinVar 2026-01 (mtDNA subset)" }, { "name": "mt_gene_coordinates", "version": "rCRS NC_012920.1" }, { "name": "mt_haplogroups", "version": "PhyloTree Build 17 (FU1a)" }, { "name": "mt_helix_curated", "version": "(empty -- clinician-populated via PR-6 UI)" }, { "name": "mt_population_frequencies", "version": "MITOMAP 2026-01 + HelixMTdb 20200327" }, { "name": "nuclear_numt_known_regions", "version": "Calabrese 2017 + Dayama 2014" }, { "name": "orphanet", "version": "2025-12" }, { "name": "pubmed", "version": "(real-time)" }, { "name": "spliceai", "version": "1.3" }, { "name": "vcep_specs", "version": "2026-03" } ], "interpretation_status": "success", "user_request": "What does NM_007294.4:c.68_69del mean? Show the evidence.", "tool_call": { "name": "search_variant_evidence", "arguments": { "assembly": "GRCh38", "query": "NM_007294.4:c.68_69del" } }, "response_guidance": "Report the verified BRCA1 deletion and the returned automated P classification with its criteria and source versions. Require professional review.", "raw_response": { "id": 1, "jsonrpc": "2.0", "result": { "_meta": { "io.modelcontextprotocol/serverInfo": { "description": "Classify and interpret supported GRCh38 germline variants under ACMG/AMP with structured evidence, provenance and related literature through the official public, read-only Helena Bioinformatics MCP.", "icons": [ { "mimeType": "image/png", "src": "https://folklore.helena.bio/images/logos/folklore.png" } ], "name": "folklore", "title": "Folklore Clinical Variant Interpretation MCP", "version": "1.4.1", "websiteUrl": "https://folklore.helena.bio" } }, "content": [ { "text": "Folklore resolved chr17:43124027 ACT>A in BRCA1. Automated ACMG/AMP class: P; criteria: PVS1,PS1,BS1_Strong[VCEP][af_grpmax] [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]. This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation. Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated. Record: https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43124027&reference=ACT&alternate=A", "type": "text" } ], "isError": false, "resultType": "complete", "structuredContent": { "adapter_error": null, "contract_version": "1", "record_url": "https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43124027&reference=ACT&alternate=A", "result": { "identity": { "alternate": "A", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43124027:ACT:A", "chromosome": "chr17", "position": 43124027, "reference": "ACT", "variant_type": "DEL" }, "interpretation": { "annotation": { "biotype": "protein_coding", "consequence": "frameshift_variant", "domains": [ "CDD:cd16498", "ENSP_mappings:1jm7", "ENSP_mappings:7jzv", "ENSP_mappings:7lyb", "ENSP_mappings:8grq", "ENSP_mappings:AF", "Gene3D:3", "PANTHER:PTHR13763", "PIRSF:PIRSF001734", "Superfamily:SSF57850" ], "exon_number": "2/23", "gene_id": "ENSG00000012048", "gene_symbol": "BRCA1", "impact": "HIGH", "transcript_id": "ENST00000357654" }, "classification": { "automated_class": "P", "confidence_score": 0.8500000238418579, "criteria": "PVS1,PS1,BS1_Strong[VCEP][af_grpmax] [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]", "framework": "acmg_2015", "pm1_evidence_availability": "not_applicable", "pm1_evidence_source": null }, "contract_version": "1.0", "display": { "hgvs_cdna": "ENST00000357654.9:c.68_69del", "hgvs_genomic": "chr17:g.43124030_43124031del", "hgvs_protein": "ENSP00000350283.3:p.Glu23ValfsTer17", "label": "chr17:43124027 ACT>A" }, "evidence": { "clinvar": { "availability": "available", "canonical_url": "https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/", "clinical_significance": "Pathogenic", "disease_names": [ "BRCA1-related_cancer_predisposition", "BRCA1-related_disorder", "Breast-ovarian_cancer,_familial,_susceptibility_to,_1", "Breast_and/or_ovarian_cancer", "Endometrial_carcinoma", "Familial_cancer_of_breast", "Fanconi_anemia,_complementation_group_S", "Hereditary_breast_ovarian_cancer_syndrome", "Hereditary_cancer-predisposing_syndrome", "Inherited_breast_cancer_and_ovarian_cancer", "Inherited_ovarian_cancer_(without_breast_cancer)", "Invasive_medullary_breast_carcinoma", "Malignant_tumor_of_breast", "Ovarian_neoplasm", "Pancreatic_cancer,_susceptibility_to,_4", "Triple-negative_breast_cancer", "not_provided" ], "protein_representation": null, "review_stars": 3, "review_status": "reviewed_by_expert_panel", "rsid": "80357914", "variation_id": "17662" }, "clinvar_review_stars": 3, "clinvar_significance": "Pathogenic", "conservation": { "availability": "no_record", "gerp_rs": null, "phylop100way_vertebrate": null }, "dosage": { "availability": "available", "haploinsufficiency_score": 3, "triplosensitivity_score": 0 }, "erepo_assertion": "Pathogenic", "erepo_disease": "BRCA1-related cancer predisposition", "erepo_panel": "ENIGMA BRCA1 and BRCA2 VCEP", "expert": { "availability": "available", "erepo_assertion": "Pathogenic", "erepo_disease": "BRCA1-related cancer predisposition", "erepo_panel": "ENIGMA BRCA1 and BRCA2 VCEP", "erepo_summary": "The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 17 of the frameshift, or amino acid 39 (p.Glu23ValfsTer17). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 3 (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 32546644) (PS3 met).In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PS3).", "erepo_url": null, "vcep_applied": true, "vcep_panel": "ENIGMA BRCA1/2" }, "external_links": { "clingen_erepo": null, "clinvar": "https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/", "ensembl_gene": "https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000012048", "ensembl_transcript": "https://www.ensembl.org/Homo_sapiens/Transcript/Summary?t=ENST00000357654", "gnomad": "https://gnomad.broadinstitute.org/variant/chr17-43124027-ACT-A?dataset=gnomad_r4" }, "gene_constraints": { "availability": "available", "loeuf": 0.927590012550354, "missense_z": 1.7336000204086304, "oe_lof": 0.8061800003051758, "pli": 5.517099828041024e-38 }, "population": { "availability": "available", "canonical_url": "https://gnomad.broadinstitute.org/variant/chr17-43124027-ACT-A?dataset=gnomad_r4", "global_allele_count": 191, "global_allele_frequency": 0.0001184799984912388, "global_allele_number": 1612084, "group_max_allele_frequency": 0.0001645279990043491, "homozygote_count": 0, "popmax_population": "nfe", "rsid": "80357914" }, "predictors": { "alphamissense": { "prediction": null, "score": null }, "availability": "no_record", "bayesdel_addaf": { "prediction": null, "score": null }, "bayesdel_noaf": { "prediction": null, "score": null }, "dann_score": null, "metasvm": { "prediction": null, "score": null }, "sift": { "prediction": null, "score": null } }, "spliceai": { "availability": "no_record", "ds_ag": null, "ds_al": null, "ds_dg": null, "ds_dl": null, "gene": null, "max_delta_score": null, "prediction": null }, "vcep_applied": true, "vcep_panel": "ENIGMA BRCA1/2" }, "identity": { "alternate": "A", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43124027:ACT:A", "chromosome": "chr17", "position": 43124027, "reference": "ACT", "variant_type": "DEL" }, "limitations": { "diagnostic_use": "This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation.", "scope": "Automated variant-level ACMG/AMP decision support for one GRCh38 nuclear SNV, simple indel, or delins smaller than 50 bp.", "unavailable_context": "Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated." }, "provenance": { "annotation_resolved": true, "annotation_source": "vep_cache", "classification_completed": true, "classifier_version": "3.39.1", "classifier_version_label": "v3.39.1", "reference_assembly": "GRCh38", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": "2026-01" }, { "name": "clinvar", "version": "2026-01" }, { "name": "dbnsfp", "version": "4.9c" }, { "name": "ensembl_vep", "version": "Release 113" }, { "name": "erepo_classifications", "version": "erepo-2026-06-04" }, { "name": "exon_pext", "version": "2.1.1" }, { "name": "g2p", "version": "2026-01" }, { "name": "gnomad", "version": "4.1" }, { "name": "gnomad_constraint", "version": "4.1" }, { "name": "gof_genes", "version": "2026-01" }, { "name": "hpo", "version": "2026-01" }, { "name": "interpro_pfam", "version": "2026-03" }, { "name": "mane_select", "version": "2.0" }, { "name": "mt_apogee2_scores", "version": "APOGEE2 v2.0" }, { "name": "mt_clinvar_variants", "version": "ClinVar 2026-01 (mtDNA subset)" }, { "name": "mt_gene_coordinates", "version": "rCRS NC_012920.1" }, { "name": "mt_haplogroups", "version": "PhyloTree Build 17 (FU1a)" }, { "name": "mt_helix_curated", "version": "(empty -- clinician-populated via PR-6 UI)" }, { "name": "mt_population_frequencies", "version": "MITOMAP 2026-01 + HelixMTdb 20200327" }, { "name": "nuclear_numt_known_regions", "version": "Calabrese 2017 + Dayama 2014" }, { "name": "orphanet", "version": "2025-12" }, { "name": "pubmed", "version": "(real-time)" }, { "name": "spliceai", "version": "1.3" }, { "name": "vcep_specs", "version": "2026-03" } ], "vep_cache_version": "ensembl-vep-113-mane-v2", "vep_version": "113" }, "status": "success", "warnings": [ "external_link_unavailable" ] }, "resolution": { "input_accession": "NM_007294.4", "input_version": "4", "mapping_sources": [ { "name": "managed_vep_cache", "version": "113" }, { "name": "mane", "version": "v1.5" } ], "normalized_query": "NM_007294.4:c.68_69del", "notation_family": "transcript_hgvs", "resolver_asset_version": "pvr-sha256-02400e1bac7f3ed7db3de7027c6e86e6a7fb6d49d1dcf61fb5d8379d1feab137", "resolver_schema_version": "public-variant-resolver-3", "warnings": [] }, "search_contract_version": "1.0", "status": "resolved" }, "usage_boundary": { "intended_use": "professional_variant_review", "not_for": [ "patient_diagnosis", "treatment_decision", "standalone_clinical_reporting" ], "patient_context_evaluated": false, "result_type": "automated_variant_level_classification", "review_required": true } } } }, "endpoint": "https://api.helena.bio/folklore/v1/mcp" }, { "case_id": "transcript-hgvs-gnrhr", "input": "ENST00000226413.5:c.317A>G", "status": "resolved", "identity": { "alternate": "C", "assembly": "GRCh38", "canonical_key": "GRCh38:chr4:67754019:T:C", "chromosome": "chr4", "position": 67754019, "reference": "T", "variant_type": "SNV" }, "automated_class": "P", "criteria": "ClinVar,PP3_Supporting", "classifier_version": "3.39.1", "evidence_availability": { "clinvar": "available", "conservation": "available", "dosage": "no_record", "expert": "no_record", "gene_constraints": "available", "population": "available", "predictors": "available", "spliceai": "available" }, "observed_at_utc": "2026-09-10T16:37:23Z", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": "2026-01" }, { "name": "clinvar", "version": "2026-01" }, { "name": "dbnsfp", "version": "4.9c" }, { "name": "ensembl_vep", "version": "Release 113" }, { "name": "erepo_classifications", "version": "erepo-2026-06-04" }, { "name": "exon_pext", "version": "2.1.1" }, { "name": "g2p", "version": "2026-01" }, { "name": "gnomad", "version": "4.1" }, { "name": "gnomad_constraint", "version": "4.1" }, { "name": "gof_genes", "version": "2026-01" }, { "name": "hpo", "version": "2026-01" }, { "name": "interpro_pfam", "version": "2026-03" }, { "name": "mane_select", "version": "2.0" }, { "name": "mt_apogee2_scores", "version": "APOGEE2 v2.0" }, { "name": "mt_clinvar_variants", "version": "ClinVar 2026-01 (mtDNA subset)" }, { "name": "mt_gene_coordinates", "version": "rCRS NC_012920.1" }, { "name": "mt_haplogroups", "version": "PhyloTree Build 17 (FU1a)" }, { "name": "mt_helix_curated", "version": "(empty -- clinician-populated via PR-6 UI)" }, { "name": "mt_population_frequencies", "version": "MITOMAP 2026-01 + HelixMTdb 20200327" }, { "name": "nuclear_numt_known_regions", "version": "Calabrese 2017 + Dayama 2014" }, { "name": "orphanet", "version": "2025-12" }, { "name": "pubmed", "version": "(real-time)" }, { "name": "spliceai", "version": "1.3" }, { "name": "vcep_specs", "version": "2026-03" } ], "interpretation_status": "success", "user_request": "Interpret ENST00000226413.5:c.317A>G and explain the returned criteria.", "tool_call": { "name": "search_variant_evidence", "arguments": { "assembly": "GRCh38", "query": "ENST00000226413.5:c.317A>G" } }, "response_guidance": "Report the verified GNRHR allele and the returned automated P classification. Explain only the returned criteria and cite the source evidence.", "raw_response": { "id": 2, "jsonrpc": "2.0", "result": { "_meta": { "io.modelcontextprotocol/serverInfo": { "description": "Classify and interpret supported GRCh38 germline variants under ACMG/AMP with structured evidence, provenance and related literature through the official public, read-only Helena Bioinformatics MCP.", "icons": [ { "mimeType": "image/png", "src": "https://folklore.helena.bio/images/logos/folklore.png" } ], "name": "folklore", "title": "Folklore Clinical Variant Interpretation MCP", "version": "1.4.1", "websiteUrl": "https://folklore.helena.bio" } }, "content": [ { "text": "Folklore resolved chr4:67754019 T>C in GNRHR. Automated ACMG/AMP class: P; criteria: ClinVar,PP3_Supporting. This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation. Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated. Record: https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr4&position=67754019&reference=T&alternate=C", "type": "text" } ], "isError": false, "resultType": "complete", "structuredContent": { "adapter_error": null, "contract_version": "1", "record_url": "https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr4&position=67754019&reference=T&alternate=C", "result": { "identity": { "alternate": "C", "assembly": "GRCh38", "canonical_key": "GRCh38:chr4:67754019:T:C", "chromosome": "chr4", "position": 67754019, "reference": "T", "variant_type": "SNV" }, "interpretation": { "annotation": { "biotype": "protein_coding", "consequence": "missense_variant", "domains": [ "ENSP_mappings:7br3", "ENSP_mappings:AF", "Gene3D:1", "PANTHER:PTHR24241", "PROSITE_profiles:PS50262", "Pfam:PF00001", "Prints:PR00529", "Superfamily:SSF81321" ], "exon_number": "1/3", "gene_id": "ENSG00000109163", "gene_symbol": "GNRHR", "impact": "MODERATE", "transcript_id": "ENST00000226413" }, "classification": { "automated_class": "P", "confidence_score": 0.8500000238418579, "criteria": "ClinVar,PP3_Supporting", "framework": "acmg_2015", "pm1_evidence_availability": "not_applicable", "pm1_evidence_source": null }, "contract_version": "1.0", "display": { "hgvs_cdna": "ENST00000226413.5:c.317A>G", "hgvs_genomic": "chr4:g.67754019T>C", "hgvs_protein": "ENSP00000226413.5:p.Gln106Arg", "label": "chr4:67754019 T>C" }, "evidence": { "clinvar": { "availability": "available", "canonical_url": "https://www.ncbi.nlm.nih.gov/clinvar/variation/16023/", "clinical_significance": "Pathogenic/Likely_pathogenic", "disease_names": [ "GNRHR-related_disorder", "Gonadotropin_deficiency", "Hypogonadotropic_hypogonadism", "Hypogonadotropic_hypogonadism_7_with_or_without_anosmia", "Inborn_genetic_diseases", "Infertility_disorder", "Isolated_congenital_hypogonadotropic_hypogonadism", "Pituitary_hormone_deficiency", "not_provided" ], "protein_representation": null, "review_stars": 2, "review_status": "criteria_provided,_multiple_submitters,_no_conflicts", "rsid": "104893836", "variation_id": "16023" }, "clinvar_review_stars": 2, "clinvar_significance": "Pathogenic/Likely_pathogenic", "conservation": { "availability": "available", "gerp_rs": 6.170000076293945, "phylop100way_vertebrate": 7.946000099182129 }, "dosage": { "availability": "no_record", "haploinsufficiency_score": null, "triplosensitivity_score": null }, "erepo_assertion": null, "erepo_disease": null, "erepo_panel": null, "expert": { "availability": "no_record", "erepo_assertion": null, "erepo_disease": null, "erepo_panel": null, "erepo_summary": null, "erepo_url": null, "vcep_applied": false, "vcep_panel": null }, "external_links": { "clingen_erepo": null, "clinvar": "https://www.ncbi.nlm.nih.gov/clinvar/variation/16023/", "ensembl_gene": "https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000109163", "ensembl_transcript": "https://www.ensembl.org/Homo_sapiens/Transcript/Summary?t=ENST00000226413", "gnomad": "https://gnomad.broadinstitute.org/variant/chr4-67754019-T-C?dataset=gnomad_r4" }, "gene_constraints": { "availability": "available", "loeuf": 0.7791299819946289, "missense_z": 0.35155999660491943, "oe_lof": 0.49838000535964966, "pli": 0.021412000060081482 }, "population": { "availability": "available", "canonical_url": "https://gnomad.broadinstitute.org/variant/chr4-67754019-T-C?dataset=gnomad_r4", "global_allele_count": 5708, "global_allele_frequency": 0.003536839969456196, "global_allele_number": 1613870, "group_max_allele_frequency": 0.005278789903968573, "homozygote_count": 10, "popmax_population": "nfe", "rsid": "104893836" }, "predictors": { "alphamissense": { "prediction": "A;B", "score": null }, "availability": "available", "bayesdel_addaf": { "prediction": "T", "score": 0.009643539786338806 }, "bayesdel_noaf": { "prediction": "D", "score": 0.2462030053138733 }, "dann_score": 0.9957625865936279, "metasvm": { "prediction": "T", "score": -0.3199000060558319 }, "sift": { 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NC_012920.1" }, { "name": "mt_haplogroups", "version": "PhyloTree Build 17 (FU1a)" }, { "name": "mt_helix_curated", "version": "(empty -- clinician-populated via PR-6 UI)" }, { "name": "mt_population_frequencies", "version": "MITOMAP 2026-01 + HelixMTdb 20200327" }, { "name": "nuclear_numt_known_regions", "version": "Calabrese 2017 + Dayama 2014" }, { "name": "orphanet", "version": "2025-12" }, { "name": "pubmed", "version": "(real-time)" }, { "name": "spliceai", "version": "1.3" }, { "name": "vcep_specs", "version": "2026-03" } ], "vep_cache_version": "ensembl-vep-113-mane-v2", "vep_version": "113" }, "status": "success", "warnings": [ "expert_evidence_not_available" ] }, "resolution": { "input_accession": "ENST00000226413.5", "input_version": "5", "mapping_sources": [ { "name": "managed_vep_cache", "version": "113" } ], "normalized_query": "ENST00000226413.5:c.317A>G", "notation_family": "transcript_hgvs", "resolver_asset_version": "pvr-sha256-02400e1bac7f3ed7db3de7027c6e86e6a7fb6d49d1dcf61fb5d8379d1feab137", "resolver_schema_version": "public-variant-resolver-3", "warnings": [] }, "search_contract_version": "1.0", "status": "resolved" }, "usage_boundary": { "intended_use": "professional_variant_review", "not_for": [ "patient_diagnosis", "treatment_decision", "standalone_clinical_reporting" ], "patient_context_evaluated": false, "result_type": "automated_variant_level_classification", "review_required": true } } } }, "endpoint": "https://api.helena.bio/folklore/v1/mcp" }, { "case_id": "canonical-brca1-deletion", "input": "GRCh38:chr17:43124027:ACT:A", "status": "resolved", "identity": { "alternate": "A", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43124027:ACT:A", "chromosome": "chr17", "position": 43124027, "reference": "ACT", "variant_type": "DEL" }, "automated_class": "P", "criteria": "PVS1,PS1,BS1_Strong[VCEP][af_grpmax] [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]", "classifier_version": "3.39.1", "evidence_availability": { "clinvar": "available", "conservation": "no_record", "dosage": "available", "expert": "available", "gene_constraints": "available", "population": "available", "predictors": "no_record", "spliceai": "no_record" }, "observed_at_utc": "2026-09-10T16:37:33Z", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": "2026-01" }, { "name": "clinvar", "version": "2026-01" }, { "name": "dbnsfp", "version": "4.9c" }, { "name": "ensembl_vep", "version": "Release 113" }, { "name": "erepo_classifications", "version": "erepo-2026-06-04" }, { "name": "exon_pext", "version": "2.1.1" }, { "name": "g2p", "version": "2026-01" }, { "name": "gnomad", "version": "4.1" }, { "name": "gnomad_constraint", "version": "4.1" }, { "name": "gof_genes", "version": "2026-01" }, { "name": "hpo", "version": "2026-01" }, { "name": "interpro_pfam", "version": "2026-03" }, { "name": "mane_select", "version": "2.0" }, { "name": "mt_apogee2_scores", "version": "APOGEE2 v2.0" }, { "name": "mt_clinvar_variants", "version": "ClinVar 2026-01 (mtDNA subset)" }, { "name": "mt_gene_coordinates", "version": "rCRS NC_012920.1" }, { "name": "mt_haplogroups", "version": "PhyloTree Build 17 (FU1a)" }, { "name": "mt_helix_curated", "version": "(empty -- clinician-populated via PR-6 UI)" }, { "name": "mt_population_frequencies", "version": "MITOMAP 2026-01 + HelixMTdb 20200327" }, { "name": "nuclear_numt_known_regions", "version": "Calabrese 2017 + Dayama 2014" }, { "name": "orphanet", "version": "2025-12" }, { "name": "pubmed", "version": "(real-time)" }, { "name": "spliceai", "version": "1.3" }, { "name": "vcep_specs", "version": "2026-03" } ], "interpretation_status": "success", "user_request": "Check the identity and evidence for GRCh38:chr17:43124027:ACT:A.", "tool_call": { "name": "search_variant_evidence", "arguments": { "assembly": "GRCh38", "query": "GRCh38:chr17:43124027:ACT:A" } }, "response_guidance": "Report the exact normalized GRCh38 allele. Keep ClinVar assertions separate from the automated classification.", "raw_response": { "id": 3, "jsonrpc": "2.0", "result": { "_meta": { "io.modelcontextprotocol/serverInfo": { "description": "Classify and interpret supported GRCh38 germline variants under ACMG/AMP with structured evidence, provenance and related literature through the official public, read-only Helena Bioinformatics MCP.", "icons": [ { "mimeType": "image/png", "src": "https://folklore.helena.bio/images/logos/folklore.png" } ], "name": "folklore", "title": "Folklore Clinical Variant Interpretation MCP", "version": "1.4.1", "websiteUrl": "https://folklore.helena.bio" } }, "content": [ { "text": "Folklore resolved chr17:43124027 ACT>A in BRCA1. Automated ACMG/AMP class: P; criteria: PVS1,PS1,BS1_Strong[VCEP][af_grpmax] [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]. This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation. Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated. Record: https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43124027&reference=ACT&alternate=A", "type": "text" } ], "isError": false, "resultType": "complete", "structuredContent": { "adapter_error": null, "contract_version": "1", "record_url": "https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43124027&reference=ACT&alternate=A", "result": { "identity": { "alternate": "A", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43124027:ACT:A", "chromosome": "chr17", "position": 43124027, "reference": "ACT", "variant_type": "DEL" }, "interpretation": { "annotation": { "biotype": "protein_coding", "consequence": "frameshift_variant", "domains": [ "CDD:cd16498", "ENSP_mappings:1jm7", "ENSP_mappings:7jzv", "ENSP_mappings:7lyb", "ENSP_mappings:8grq", "ENSP_mappings:AF", "Gene3D:3", "PANTHER:PTHR13763", "PIRSF:PIRSF001734", "Superfamily:SSF57850" ], "exon_number": "2/23", "gene_id": "ENSG00000012048", "gene_symbol": "BRCA1", "impact": "HIGH", "transcript_id": "ENST00000357654" }, "classification": { "automated_class": "P", "confidence_score": 0.8500000238418579, "criteria": "PVS1,PS1,BS1_Strong[VCEP][af_grpmax] [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]", "framework": "acmg_2015", "pm1_evidence_availability": "not_applicable", "pm1_evidence_source": null }, "contract_version": "1.0", "display": { "hgvs_cdna": "ENST00000357654.9:c.68_69del", "hgvs_genomic": "chr17:g.43124030_43124031del", "hgvs_protein": "ENSP00000350283.3:p.Glu23ValfsTer17", "label": "chr17:43124027 ACT>A" }, "evidence": { "clinvar": { "availability": "available", "canonical_url": "https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/", "clinical_significance": "Pathogenic", "disease_names": [ "BRCA1-related_cancer_predisposition", "BRCA1-related_disorder", "Breast-ovarian_cancer,_familial,_susceptibility_to,_1", "Breast_and/or_ovarian_cancer", "Endometrial_carcinoma", "Familial_cancer_of_breast", "Fanconi_anemia,_complementation_group_S", "Hereditary_breast_ovarian_cancer_syndrome", "Hereditary_cancer-predisposing_syndrome", "Inherited_breast_cancer_and_ovarian_cancer", "Inherited_ovarian_cancer_(without_breast_cancer)", "Invasive_medullary_breast_carcinoma", "Malignant_tumor_of_breast", "Ovarian_neoplasm", "Pancreatic_cancer,_susceptibility_to,_4", "Triple-negative_breast_cancer", "not_provided" ], "protein_representation": null, "review_stars": 3, "review_status": "reviewed_by_expert_panel", "rsid": "80357914", "variation_id": "17662" }, "clinvar_review_stars": 3, "clinvar_significance": "Pathogenic", "conservation": { "availability": "no_record", "gerp_rs": null, "phylop100way_vertebrate": null }, "dosage": { "availability": "available", "haploinsufficiency_score": 3, "triplosensitivity_score": 0 }, "erepo_assertion": "Pathogenic", "erepo_disease": "BRCA1-related cancer predisposition", "erepo_panel": "ENIGMA BRCA1 and BRCA2 VCEP", "expert": { "availability": "available", "erepo_assertion": "Pathogenic", "erepo_disease": "BRCA1-related cancer predisposition", "erepo_panel": "ENIGMA BRCA1 and BRCA2 VCEP", "erepo_summary": "The c.68_69del variant in BRCA1 is a deletion of two nucleotides, predicted to encode a frameshift with consequent premature termination of the protein at codon 17 of the frameshift, or amino acid 39 (p.Glu23ValfsTer17). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 3 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA1, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA1 exon 3 (PM5_Strong (PTC)). Reported by one calibrated study to exhibit protein function similar to pathogenic control variants (PMID: 32546644) (PS3 met).In summary, this variant meets the criteria to be classified as a Pathogenic variant variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PS3).", "erepo_url": null, "vcep_applied": true, "vcep_panel": "ENIGMA BRCA1/2" }, "external_links": { "clingen_erepo": null, "clinvar": "https://www.ncbi.nlm.nih.gov/clinvar/variation/17662/", "ensembl_gene": "https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000012048", "ensembl_transcript": "https://www.ensembl.org/Homo_sapiens/Transcript/Summary?t=ENST00000357654", "gnomad": "https://gnomad.broadinstitute.org/variant/chr17-43124027-ACT-A?dataset=gnomad_r4" }, "gene_constraints": { "availability": "available", "loeuf": 0.927590012550354, "missense_z": 1.7336000204086304, "oe_lof": 0.8061800003051758, "pli": 5.517099828041024e-38 }, "population": { "availability": "available", "canonical_url": "https://gnomad.broadinstitute.org/variant/chr17-43124027-ACT-A?dataset=gnomad_r4", "global_allele_count": 191, "global_allele_frequency": 0.0001184799984912388, "global_allele_number": 1612084, "group_max_allele_frequency": 0.0001645279990043491, "homozygote_count": 0, "popmax_population": "nfe", "rsid": "80357914" }, "predictors": { "alphamissense": { "prediction": null, "score": null }, "availability": "no_record", "bayesdel_addaf": { "prediction": null, "score": null }, "bayesdel_noaf": { "prediction": null, "score": null }, "dann_score": null, "metasvm": { "prediction": null, "score": null }, "sift": { "prediction": null, "score": null } }, "spliceai": { "availability": "no_record", "ds_ag": null, "ds_al": null, "ds_dg": null, "ds_dl": null, "gene": null, "max_delta_score": null, "prediction": null }, "vcep_applied": true, "vcep_panel": "ENIGMA BRCA1/2" }, "identity": { "alternate": "A", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43124027:ACT:A", "chromosome": "chr17", "position": 43124027, "reference": "ACT", "variant_type": "DEL" }, "limitations": { "diagnostic_use": "This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation.", "scope": "Automated variant-level ACMG/AMP decision support for one GRCh38 nuclear SNV, simple indel, or delins smaller than 50 bp.", "unavailable_context": "Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated." }, "provenance": { "annotation_resolved": true, "annotation_source": "vep_cache", "classification_completed": true, "classifier_version": "3.39.1", "classifier_version_label": "v3.39.1", "reference_assembly": "GRCh38", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": "2026-01" }, { "name": "clinvar", "version": "2026-01" }, { "name": 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"result_type": "automated_variant_level_classification", "review_required": true } } } }, "endpoint": "https://api.helena.bio/folklore/v1/mcp" }, { "case_id": "vus-brca1", "input": "chr17:43115777 A>G", "status": "resolved", "identity": { "alternate": "G", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43115777:A:G", "chromosome": "chr17", "position": 43115777, "reference": "A", "variant_type": "SNV" }, "automated_class": "VUS", "criteria": "PM1,PM2_Supporting [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]", "classifier_version": "3.39.1", "evidence_availability": { "clinvar": "available", "conservation": "available", "dosage": "available", "expert": "available", "gene_constraints": "available", "population": "no_record", "predictors": "available", "spliceai": "available" }, "observed_at_utc": "2026-09-10T16:37:43Z", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": 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"MITOMAP 2026-01 + HelixMTdb 20200327" }, { "name": "nuclear_numt_known_regions", "version": "Calabrese 2017 + Dayama 2014" }, { "name": "orphanet", "version": "2025-12" }, { "name": "pubmed", "version": "(real-time)" }, { "name": "spliceai", "version": "1.3" }, { "name": "vcep_specs", "version": "2026-03" } ], "interpretation_status": "success", "user_request": "Review this VUS: chr17:43115777 A>G on GRCh38.", "tool_call": { "name": "search_variant_evidence", "arguments": { "assembly": "GRCh38", "query": "chr17:43115777 A>G" } }, "response_guidance": "Report VUS with the returned criteria and evidence availability. Do not relabel uncertainty as pathogenic or benign.", "raw_response": { "id": 4, "jsonrpc": "2.0", "result": { "_meta": { "io.modelcontextprotocol/serverInfo": { "description": "Classify and interpret supported GRCh38 germline variants under ACMG/AMP with structured evidence, provenance and related literature through the official public, read-only Helena Bioinformatics MCP.", "icons": [ { "mimeType": "image/png", "src": "https://folklore.helena.bio/images/logos/folklore.png" } ], "name": "folklore", "title": "Folklore Clinical Variant Interpretation MCP", "version": "1.4.1", "websiteUrl": "https://folklore.helena.bio" } }, "content": [ { "text": "Folklore resolved chr17:43115777 A>G in BRCA1. Automated ACMG/AMP class: VUS; criteria: PM1,PM2_Supporting [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]. This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation. Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated. Record: https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43115777&reference=A&alternate=G", "type": "text" } ], "isError": false, "resultType": "complete", "structuredContent": { "adapter_error": null, "contract_version": "1", "record_url": "https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43115777&reference=A&alternate=G", "result": { "identity": { "alternate": "G", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43115777:A:G", "chromosome": "chr17", "position": 43115777, "reference": "A", "variant_type": "SNV" }, "interpretation": { "annotation": { "biotype": "protein_coding", "consequence": "missense_variant,splice_region_variant", "domains": [ "CDD:cd16498", "ENSP_mappings:1jm7", "ENSP_mappings:7jzv", "ENSP_mappings:7lyb", "ENSP_mappings:8grq", "ENSP_mappings:AF", "Gene3D:3", "PANTHER:PTHR13763", "PIRSF:PIRSF001734", "PROSITE_profiles:PS50089", "Pfam:PF00097", "SMART:SM00184", "Superfamily:SSF57850" ], "exon_number": "3/23", "gene_id": "ENSG00000012048", "gene_symbol": "BRCA1", "impact": "MODERATE", "transcript_id": "ENST00000357654" }, "classification": { "automated_class": "VUS", "confidence_score": 0.5, "criteria": "PM1,PM2_Supporting [VCEP:ENIGMA BRCA1/2 v1.2.0] [ERepo:ENIGMA BRCA1 and BRCA2 VCEP,BRCA1-related cancer predisposition]", "framework": "acmg_2015", "pm1_evidence_availability": "available", "pm1_evidence_source": "pfam" }, "contract_version": "1.0", "display": { "hgvs_cdna": "ENST00000357654.9:c.83T>C", "hgvs_genomic": "chr17:g.43115777A>G", "hgvs_protein": "ENSP00000350283.3:p.Leu28Pro", "label": "chr17:43115777 A>G" }, "evidence": { "clinvar": { "availability": "available", "canonical_url": "https://www.ncbi.nlm.nih.gov/clinvar/variation/55732/", "clinical_significance": "Uncertain_significance", "disease_names": [ "BRCA1-related_cancer_predisposition", "Breast-ovarian_cancer,_familial,_susceptibility_to,_1", "Hereditary_breast_ovarian_cancer_syndrome", "Hereditary_cancer-predisposing_syndrome", "not_provided", "not_specified" ], "protein_representation": null, "review_stars": 3, "review_status": "reviewed_by_expert_panel", "rsid": "80357266", "variation_id": "55732" }, "clinvar_review_stars": 3, "clinvar_significance": "Uncertain_significance", "conservation": { "availability": "available", "gerp_rs": 5.96999979019165, "phylop100way_vertebrate": 4.109000205993652 }, "dosage": { "availability": "available", "haploinsufficiency_score": 3, "triplosensitivity_score": 0 }, "erepo_assertion": "Uncertain Significance", "erepo_disease": "BRCA1-related cancer predisposition", "erepo_panel": "ENIGMA BRCA1 and BRCA2 VCEP", "expert": { "availability": "available", "erepo_assertion": "Uncertain Significance", "erepo_disease": "BRCA1-related cancer predisposition", "erepo_panel": "ENIGMA BRCA1 and BRCA2 VCEP", "erepo_summary": "The c.83T>C variant in BRCA1 is a missense variant predicted to cause substitution of Leucine by Proline at amino acid 28 (p.(Leu28Pro)). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth \u226525) and gnomAD v3.1 (non-cancer subset, read depth \u226525) (PM2_Supporting met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMID:30209399, 35659930) (PS3 met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.45, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.41 (based on Co-occurrence LR=1.07; Family History LR=0.38), within the thresholds for supporting benign evidence (LR 0.23-0.48) (BP5 met; Internal lab contributor). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PS3, PP3, BP5).", "erepo_url": null, "vcep_applied": true, "vcep_panel": "ENIGMA BRCA1/2" }, "external_links": { "clingen_erepo": null, "clinvar": "https://www.ncbi.nlm.nih.gov/clinvar/variation/55732/", "ensembl_gene": "https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000012048", "ensembl_transcript": "https://www.ensembl.org/Homo_sapiens/Transcript/Summary?t=ENST00000357654", "gnomad": null }, "gene_constraints": { "availability": "available", "loeuf": 0.927590012550354, "missense_z": 1.7336000204086304, "oe_lof": 0.8061800003051758, "pli": 5.517099828041024e-38 }, "population": { "availability": "no_record", "canonical_url": null, "global_allele_count": null, "global_allele_frequency": null, "global_allele_number": null, 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"diagnostic_use": "This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation.", "scope": "Automated variant-level ACMG/AMP decision support for one GRCh38 nuclear SNV, simple indel, or delins smaller than 50 bp.", "unavailable_context": "Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated." }, "provenance": { "annotation_resolved": true, "annotation_source": "vep_cache", "classification_completed": true, "classifier_version": "3.39.1", "classifier_version_label": "v3.39.1", "reference_assembly": "GRCh38", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": "2026-01" }, { "name": "clinvar", "version": "2026-01" }, { "name": "dbnsfp", "version": "4.9c" }, { "name": "ensembl_vep", "version": "Release 113" }, { "name": "erepo_classifications", "version": "erepo-2026-06-04" }, { "name": "exon_pext", 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"chr17:43104953 G>C", "status": "resolved", "identity": { "alternate": "C", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43104953:G:C", "chromosome": "chr17", "position": 43104953, "reference": "G", "variant_type": "SNV" }, "automated_class": "VUS", "criteria": "PP3_Supporting [VCEP:ENIGMA BRCA1/2 v1.2.0]", "classifier_version": "3.39.1", "evidence_availability": { "clinvar": "available", "conservation": "available", "dosage": "available", "expert": "available", "gene_constraints": "available", "population": "available", "predictors": "available", "spliceai": "available" }, "observed_at_utc": "2026-09-10T16:37:53Z", "reference_versions": [ { "name": "clingen_dosage", "version": "2026-01" }, { "name": "clingen_gdv", "version": "2026-01" }, { "name": "clinvar", "version": "2026-01" }, { "name": "dbnsfp", "version": "4.9c" }, { "name": "ensembl_vep", "version": "Release 113" }, { "name": "erepo_classifications", "version": "erepo-2026-06-04" }, { "name": "exon_pext", "version": "2.1.1" }, { "name": "g2p", "version": "2026-01" }, { "name": "gnomad", "version": "4.1" }, { "name": "gnomad_constraint", "version": "4.1" }, { "name": "gof_genes", "version": "2026-01" }, { "name": "hpo", "version": "2026-01" }, { "name": "interpro_pfam", "version": "2026-03" }, { "name": "mane_select", "version": "2.0" }, { "name": "mt_apogee2_scores", "version": "APOGEE2 v2.0" }, { "name": "mt_clinvar_variants", "version": "ClinVar 2026-01 (mtDNA subset)" }, { "name": "mt_gene_coordinates", "version": "rCRS NC_012920.1" }, { "name": "mt_haplogroups", "version": "PhyloTree Build 17 (FU1a)" }, { "name": "mt_helix_curated", "version": "(empty -- clinician-populated via PR-6 UI)" }, { "name": "mt_population_frequencies", "version": "MITOMAP 2026-01 + HelixMTdb 20200327" }, { "name": "nuclear_numt_known_regions", "version": "Calabrese 2017 + Dayama 2014" }, { "name": "orphanet", "version": "2025-12" }, { "name": "pubmed", "version": "(real-time)" }, { "name": "spliceai", "version": "1.3" }, { "name": "vcep_specs", "version": "2026-03" } ], "interpretation_status": "success", "user_request": "Review the classification and available source assertions for chr17:43104953 G>C on GRCh38.", "tool_call": { "name": "search_variant_evidence", "arguments": { "assembly": "GRCh38", "query": "chr17:43104953 G>C" } }, "response_guidance": "Keep the automated VUS result separate from individual source assertions and preserve their review states and provenance.", "raw_response": { "id": 5, "jsonrpc": "2.0", "result": { "_meta": { "io.modelcontextprotocol/serverInfo": { "description": "Classify and interpret supported GRCh38 germline variants under ACMG/AMP with structured evidence, provenance and related literature through the official public, read-only Helena Bioinformatics MCP.", "icons": [ { "mimeType": "image/png", "src": "https://folklore.helena.bio/images/logos/folklore.png" } ], "name": "folklore", "title": "Folklore Clinical Variant Interpretation MCP", "version": 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Automated ACMG/AMP class: VUS; criteria: PP3_Supporting [VCEP:ENIGMA BRCA1/2 v1.2.0]. This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation. Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated. Record: https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43104953&reference=G&alternate=C", "type": "text" } ], "isError": false, "resultType": "complete", "structuredContent": { "adapter_error": null, "contract_version": "1", "record_url": "https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr17&position=43104953&reference=G&alternate=C", "result": { "identity": { "alternate": "C", "assembly": "GRCh38", "canonical_key": "GRCh38:chr17:43104953:G:C", "chromosome": "chr17", "position": 43104953, "reference": "G", "variant_type": "SNV" }, "interpretation": { "annotation": { "biotype": "protein_coding", "consequence": "missense_variant", "domains": [ "CDD:cd16498", "ENSP_mappings:1jm7", "ENSP_mappings:7jzv", "ENSP_mappings:7lyb", "ENSP_mappings:8grq", "ENSP_mappings:AF", "Gene3D:3", "PANTHER:PTHR13763", "PIRSF:PIRSF001734", "Superfamily:SSF57850" ], "exon_number": "5/23", "gene_id": "ENSG00000012048", "gene_symbol": "BRCA1", "impact": "MODERATE", 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"resolver_asset_version": "pvr-sha256-02400e1bac7f3ed7db3de7027c6e86e6a7fb6d49d1dcf61fb5d8379d1feab137", "resolver_schema_version": "public-variant-resolver-3", "warnings": [] }, "search_contract_version": "1.0", "status": "resolved" }, "usage_boundary": { "intended_use": "professional_variant_review", "not_for": [ "patient_diagnosis", "treatment_decision", "standalone_clinical_reporting" ], "patient_context_evaluated": false, "result_type": "automated_variant_level_classification", "review_required": true } } } }, "endpoint": "https://api.helena.bio/folklore/v1/mcp" }, { "case_id": "rsid-multiallelic-brca1", "input": "rs80357914", "status": "ambiguous", "identity": null, "automated_class": null, "criteria": null, "classifier_version": null, "evidence_availability": { "clinvar": "not_reported", "conservation": "not_reported", "dosage": "not_reported", "expert": "not_reported", "gene_constraints": "not_reported", "population": "not_reported", "predictors": "not_reported", "spliceai": "not_reported" }, "observed_at_utc": "2026-09-10T16:38:03Z", "reference_versions": [], "interpretation_status": null, "user_request": "Interpret rs80357914.", "tool_call": { "name": "search_variant_evidence", "arguments": { "assembly": "GRCh38", "query": "rs80357914" } }, "response_guidance": "Show the returned candidates and request an exact allele. Do not select the first candidate or report a classification.", "raw_response": { "id": 6, "jsonrpc": "2.0", "result": { "_meta": { "io.modelcontextprotocol/serverInfo": { "description": "Classify and interpret supported GRCh38 germline variants under ACMG/AMP with structured evidence, provenance and related literature through the official public, read-only Helena Bioinformatics MCP.", "icons": [ { "mimeType": "image/png", "src": "https://folklore.helena.bio/images/logos/folklore.png" } ], "name": "folklore", "title": "Folklore Clinical Variant Interpretation MCP", "version": "1.4.1", "websiteUrl": "https://folklore.helena.bio" } }, "content": [ { "text": "The query is ambiguous and has 2 supported GRCh38 candidates. 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It is not a patient risk assessment or reassurance.", "raw_response": { "id": 8, "jsonrpc": "2.0", "result": { "_meta": { "io.modelcontextprotocol/serverInfo": { "description": "Classify and interpret supported GRCh38 germline variants under ACMG/AMP with structured evidence, provenance and related literature through the official public, read-only Helena Bioinformatics MCP.", "icons": [ { "mimeType": "image/png", "src": "https://folklore.helena.bio/images/logos/folklore.png" } ], "name": "folklore", "title": "Folklore Clinical Variant Interpretation MCP", "version": "1.4.1", "websiteUrl": "https://folklore.helena.bio" } }, "content": [ { "text": "Folklore resolved chr19:44908684 T>C in APOE. Automated ACMG/AMP class: B; criteria: BA1,BS2,BP4. This result is not a patient diagnosis and must not be used as a substitute for qualified clinical interpretation. Patient phenotype, genotype, family, segregation, de novo, case-specific, and private override evidence were not evaluated. Record: https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr19&position=44908684&reference=T&alternate=C", "type": "text" } ], "isError": false, "resultType": "complete", "structuredContent": { "adapter_error": null, "contract_version": "1", "record_url": "https://folklore.helena.bio/variant?assembly=GRCh38&chromosome=chr19&position=44908684&reference=T&alternate=C", "result": { "identity": { "alternate": "C", "assembly": "GRCh38", "canonical_key": "GRCh38:chr19:44908684:T:C", "chromosome": "chr19", "position": 44908684, "reference": "T", "variant_type": "SNV" }, "interpretation": { "annotation": { "biotype": "protein_coding", "consequence": "missense_variant", "domains": [ "ENSP_mappings:1b68", "ENSP_mappings:1bz4", "ENSP_mappings:1ea8", "ENSP_mappings:1gs9", "ENSP_mappings:1h7i", "ENSP_mappings:1le2", "ENSP_mappings:1le4", "ENSP_mappings:1lpe", "ENSP_mappings:1nfn", "ENSP_mappings:1nfo", "ENSP_mappings:1or2", "ENSP_mappings:1or3", "ENSP_mappings:2kc3", 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"canonical_url": "https://www.ncbi.nlm.nih.gov/clinvar/variation/17864/", "clinical_significance": "Conflicting_classifications_of_pathogenicity|other|risk_factor", "disease_names": [ "Alzheimer_disease", "Alzheimer_disease_2", "Alzheimer_disease_4", "Familial_hypercholesterolemia", "Lipoprotein_glomerulopathy", "Primary_degenerative_dementia_of_the_Alzheimer_type,_presenile_onset", "Warfarin_response", "not_provided", "not_specified" ], "protein_representation": null, "review_stars": 0, "review_status": "criteria_provided,_conflicting_classifications", "rsid": "429358", "variation_id": "17864" }, "clinvar_review_stars": 0, "clinvar_significance": "Conflicting_classifications_of_pathogenicity|other|risk_factor", "conservation": { "availability": "available", "gerp_rs": 3.0199999809265137, "phylop100way_vertebrate": 0.8399999737739563 }, "dosage": { "availability": "no_record", "haploinsufficiency_score": null, "triplosensitivity_score": null }, "erepo_assertion": null, "erepo_disease": null, "erepo_panel": null, "expert": { "availability": "no_record", "erepo_assertion": null, "erepo_disease": null, "erepo_panel": null, "erepo_summary": null, "erepo_url": null, "vcep_applied": false, "vcep_panel": null }, "external_links": { "clingen_erepo": null, "clinvar": "https://www.ncbi.nlm.nih.gov/clinvar/variation/17864/", "ensembl_gene": "https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000130203", "ensembl_transcript": "https://www.ensembl.org/Homo_sapiens/Transcript/Summary?t=ENST00000252486", "gnomad": "https://gnomad.broadinstitute.org/variant/chr19-44908684-T-C?dataset=gnomad_r4" }, "gene_constraints": { "availability": "available", "loeuf": 1.2948999404907227, "missense_z": -0.22622999548912048, "oe_lof": 0.7633799910545349, "pli": 0.0014179999707266688 }, "population": { "availability": "available", "canonical_url": "https://gnomad.broadinstitute.org/variant/chr19-44908684-T-C?dataset=gnomad_r4", "global_allele_count": 232864, "global_allele_frequency": 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