{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/011221f1-ca1b-4750-9435-03f4f4380288/doc/sepio/version/1.1.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1529292791", "label": "ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "2.1.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0021056", "id": "MONDO:0021056", "label": "familial adenomatous polyposis 1", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1711", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/ei/1/1712", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1711/1713", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "comments": "This variant has been observed in heterozygous state in 7 healthy unrelated adult individuals worth ≥ 6 healthy individual points in total (BS2_Supporting; [Ambry Genetics, Invitae, UK Biobank, 100,000 Genomes Project]). ", "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1711/1713", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/1/1712", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1711", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "comments": "The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000004 (1/251004 alleles), which is lower than the HCCP VCEP threshold 0.00001 for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). ", "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1636", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1606", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/ei/1/1607", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1606/1608", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "comments": "This variant has been reported in three families with a polyposis phenotype, resulting in a total phenotype score of 1.5 points (PS4_Supporting, [PMID: 11754114 and 12007223; CanVIG-UK]). ", "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1606/1608", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/1/1607", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1606", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA16021325/MONDO:0021056/089/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50099_EP167879163953841", "id": "CG-PCER-AGENT:CG_50099_EP167879163953841", "type": "Agent" }, "comments": "The NM_000038.6(APC):c.1042C>T variant in APC is predicted to cause a premature stop codon (p.R348Ter) located between codon 49 and 2645 in biologically relevant exon 10 (coding exon 9) in a gene in which loss-of-function is an established disease mechanism. However, based on unpublished RNA analyses from Ambry Genetics, the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) does not consider this variant to be applicable to PVS1. The RNA analyses showed that this variant results in an in-frame aberrant transcript lacking part of exon 10 [r.934_1074del (p.V312_Q358del)]. In addition, an increased expression of a naturally occurring alternative transcript (r.934_1236del (p.V312_Q412del), known as “exon 9a”) was observed relative to controls. The predicted premature stop codon (p.R348Ter) was excluded from both the aberrant and naturally occurring transcripts and might provide a rescue mechanism for this nonsense alteration. ", "contributionDate": { "date": "2025/5/16", "description": "Date on which this evidence was provided" }, "contributionRole": { "@id": "https://obofoundry.org/sepio/0000156", "id": "SEPIO:0000516", "label": "curator role", "type": "ContributoryRole" }, "type": "Contribution" } ], "id": "CA16021325/MONDO:0021056/089/ci/CA16021325/MONDO:0021056/089.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089/0/1594", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA16021325/MONDO:0021056/089", "metadata": { "created": "2025-05-16T17:23:39.338Z", "note": "DISCLAIMER: While the data/content in this document is approved by ClinGen expert panel(s), the SEPIO schema presented here is an initial prototype and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema.", "producedAtUTC": "Fri, 16 May 2025 17:23:39 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.1.0" }, "statementOutcome": { "@id": "https://loinc.org/LA26333-7", "id": "LN:LA26333-7", "label": "Uncertain Significance" }, "type": "VariantPathogenicityInterpretation", "uuid": "011221f1-ca1b-4750-9435-03f4f4380288", "variant": { "@id": "https://reg.genome.network/allele/CA16021325", "id": "CAR:CA16021325", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000038.6:c.1042C>T" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000038.6(APC):c.1042C>T (p.Arg348Ter)" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-14T21:54:55.973Z" } }, "status": { "code": 200, "name": "OK" } }