ACMG Variant Classification

Overview

A standardized framework for interpreting the pathogenicity of germline sequence variants, published by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP). Variants are classified into five tiers: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), and benign (B), based on combinations of evidence criteria (population frequency, computational predictions, functional data, co-segregation, de novo status, etc.).

Used by

• Applied to classify germline variants in 25 HBOC-associated genes identified by whole-exome sequencing in 372 pediatric cancer patients; 28 LP/PVs were detected across 27 patients (7.3%), alongside 187 VUS among 593 total variants in 297 patients PMID:29489754

Notes

• Classification was performed using standard diagnostic guidelines as described by ACMG/AMP.
• The distinction between likely pathogenic and pathogenic is clinically meaningful for cascade testing and risk counseling.
• VUS interpretation remains a major challenge, particularly for missense variants in genes with limited functional data.

Sources

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