{ "data": { "@context": "https://erepo.genome.network/evrepo/api/context", "@id": "https://cgerepoapi/evrepo/api/summary/classification/0043a430-c2aa-48e8-a061-fce180f7f478/doc/sepio/version/1.0.0", "assertionMethod": { "@id": "https://cspec.genome.network/cspec/SequenceVariantInterpretation/id/1535438831", "label": "ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.1.0", "type": "VariantPathogenicityInterpretationGuideline", "version": "1.1.0" }, "condition": { "@id": "https://api.monarchinitiative.org/api/bioentity/phenotype/MONDO:0700269", "id": "MONDO:0700269", "label": "BRCA2-related cancer predisposition", "type": "GeneticCondition" }, "evidenceLine": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/el/0/1594", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/ei/1/1595", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "contributionDate": { "date": "2026/7/15", "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/CA1139663185/MONDO:0700269/097/el/0/1594/1596", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "comments": "This variant is reported to result in aberrant mRNA splicing. RT-PCR demonstrated that the variant impacts splicing by causing retention of 46 bases of the 5′-end of intron 21 (out-of-frame). The percent reference (full-length, FL) and aberrant transcripts produced from the variant allele could not be determined (PMID: 31143303). RT-PCRseq confirms intron retention and the percent of aberrant transcripts produced was 65-75%, with all reads of the aberrant transcript containing the variant allele, using a non-allele specific quantitative assessment with sequence analysis (Ambry internal data). The VCEP estimate 25-35% full-length transcript is produced by the variant allele. Conservatively, the VCEP determined appropriate code strength by comparison of results to PVS1 decision tree and Rubric of weighing mRNA data (Appendix Table 9): PVS1_N/A (RNA).", "contributionDate": { "date": "2026/7/15", "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": "CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1594/1596", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/1/1595", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Not Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1594", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/el/0/1765", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/ei/1/1766", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "contributionDate": { "date": "2026/7/15", "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/CA1139663185/MONDO:0700269/097/el/0/1765/1767", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "comments": "at Strong Level:\nThe variant under assessment is located outside the canonical dinucleotide, and has been assigned PP3 based on splicing predictions. Another variant at the same nucleotide position (c.8754+5G>A) is classified as pathogenic by the ENIGMA BRCA1/2 VCEP. The SpliceAI predictions indicate that the two variants are likely to lead to the same event (disruption of the donor splice site of intron 21 in BRCA2). These observations suggest that the variant has an impact on splicing consistent with pathogenicity (PS1 (Splicing) met).", "contributionDate": { "date": "2026/7/15", "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": "CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1765/1767", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/1/1766", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1765", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/el/0/1828", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/ei/1/1829", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "contributionDate": { "date": "2026/7/15", "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/CA1139663185/MONDO:0700269/097/el/0/1828/1830", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "comments": "Reported by two calibrated studies incorporating mRNA splicing effects to exhibit protein function similar to pathogenic control variants (PMIDs :39779857, 39779848) (PS3 met).", "contributionDate": { "date": "2026/7/15", "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": "CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1828/1830", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/1/1829", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1828", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/el/0/1747", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/ei/1/1748", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "contributionDate": { "date": "2026/7/15", "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/CA1139663185/MONDO:0700269/097/el/0/1747/1749", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "comments": "This BRCA2 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.94, predicting an impact on splicing (score threshold >0.20) (PP3 met).", "contributionDate": { "date": "2026/7/15", "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": "CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1747/1749", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/1/1748", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1747", "type": "EvidenceLine" }, { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/el/0/1636", "evidenceItem": [ { "@id": "https://erepo.genome.network/evrepo/api/interpretation/CA1139663185/MONDO:0700269/097/ei/1/1637", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "contributionDate": { "date": "2026/7/15", "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/CA1139663185/MONDO:0700269/097/el/0/1636/1638", "evidenceItem": [ { "@id": "CG-PCER:curatorInference/CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "contribution": [ { "agent": { "@id": "https://erepo.genome.network/evrepo/api//agent/CG_50087_EP169680482377844", "id": "CG-PCER-AGENT:CG_50087_EP169680482377844", "type": "Agent" }, "comments": "This variant is absent from gnomAD v4.1 (read depth ≥25x in >90% samples, PM2_Supporting met).", "contributionDate": { "date": "2026/7/15", "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": "CA1139663185/MONDO:0700269/097/ci/CA1139663185/MONDO:0700269/097.002", "type": "InfFromBkgrndSciKnow" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1636/1638", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/1/1637", "statementOutcome": { "@id": "SEPIO:0000224", "label": "Met" }, "type": "CriterionAssessment" } ], "evidenceStrength": { "@id": "https://obofoundry.org/sepio" }, "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097/0/1636", "type": "EvidenceLine" } ], "id": "CG-PCER-VARINT:CA1139663185/MONDO:0700269/097", "metadata": { "created": "2026-07-15T07:18:21.328Z", "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": "Wed, 15 Jul 2026 07:18:21 -0000", "schemaLabel": "Evidence Repository.Beta-1 (Unofficial)", "version": "1.0.0" }, "statementOutcome": { "@id": "https://loinc.org/LA6668-3", "id": "LN:LA6668-3", "label": "Pathogenic" }, "type": "VariantPathogenicityInterpretation", "uuid": "0043a430-c2aa-48e8-a061-fce180f7f478", "variant": { "@id": "https://reg.genome.network/allele/CA1139663185", "id": "CAR:CA1139663185", "relatedContextualAllele": [ { "alleleName": [ { "name": "NM_000059.4:c.8754+5G>C" } ], "preferred": true } ], "relatedIdentifier": [ { "label": "NM_000059.4(BRCA2):c.8754+5G>C" } ], "type": "CAR" } }, "metadata": { "rendered": { "by": "https://erepo.genome.network/evrepo/api/summary/srvc", "when": "2026-10-13T20:14:05.817Z" } }, "status": { "code": 200, "name": "OK" } }