Acmg Variant Interpretation Memo

Use when a variant scientist, clinical molecular geneticist (ABMGG), clinical molecular pathologist (ABP-MGP), laboratory genetic counselor, or clinical-laboratory bioinformatician at a CAP / CLIA / ISO 15189 / NATA-accredited clinical genomics laboratory needs to draft an internal variant-interpretation memo for a single germline sequence variant ahead of clinical-report sign-out. Aligned to ACMG/AMP 2015 (Richards et al., Genet Med 2015) with ClinGen Sequence Variant Interpretation (SVI) Working Group refinements (PVS1 decision tree, PS1 / PM5 splicing, PS3 / BS3 functional, PP1 / BS4 segregation, PP3 / BP4 calibrated computational, PP4 phenotype-specificity, PM2_Supporting), and to any active ClinGen Variant Curation Expert Panel (VCEP) gene-specific specifications. Guides scoped intake of pseudonymised proband identifier, testing indication, HPO-coded phenotype, pedigree with named relatives and affected status, consanguinity, self-reported ancestry (for frequency comparison only — never to assign risk), ordering clinician and laboratory, assay type, reference assembly (GRCh37 / GRCh38) and transcript source (MANE Select / MANE Plus Clinical / laboratory canonical); validates HGVS gene-coding-protein nomenclature; tabulates gnomAD population frequency with the SVI PM2_Supporting refinement, REVEL / SpliceAI / AlphaMissense / CADD computational evidence with the SVI calibrated thresholds, functional / splicing / segregation / case-level / phenotype-specificity evidence under the SVI evidence-strength rubric; applies every triggered ACMG/AMP rule (PVS1, PS1–PS4, PM1–PM6, PP1–PP5, BA1, BS1–BS4, BP1–BP7) with the SVI evidence-strength modifier and a one-sentence justification per rule; assigns final classification under the ACMG/AMP combining rules — Pathogenic / Likely Pathogenic / Uncertain Significance / Likely Benign / Benign — reconciled against any ClinGen VCEP-applied classification; and produces a DRAFT variant-interpretation memo, evidence ledger, ACMG/AMP rule trace, ClinVar-submission-ready record, recommended downstream actions, and laboratory-director and clinical-genetic-counselor review-and-sign-out block — for the certifying laboratory director's review before any CAP / CLIA / ISO 15189 clinical report is issued. Never issues a clinical report, never substitutes for the certifying laboratory director's sign-out, never substitutes for a board-certified clinical molecular geneticist / clinical molecular pathologist / laboratory genetic counselor, never performs primary variant calling or assay validation, never returns ACMG SF-list secondary findings without explicit scope confirmation, never performs tumour-somatic variant tier-classification (AMP/ASCO/CAP 2017 — different framework), and never replaces patient-facing genetic counseling.

by @archlab-space (devasher)·MIT-0