Kidney Week 2025 Early Program - Genetics in Clinical Nephrology-ACMG AMP Variant Classification Standards Cheat Sheet

ACMG AMP Variant Classification Standards Cheat Sheet

Pdf Summary

This document summarizes the main evidence types used to classify genetic sequence variants under the ACMG/AMP standards (“Standards and guidelines for the interpretation of sequence variants,” Richards et al., <em>Genetics in Medicine</em>, 2015). These standards (referred to here as SVCv3) define evidence categories, specific evidence lines, and associated evidence codes that can be applied at different strength levels to support either benign or pathogenic interpretations.

Two broad evidence categories are highlighted: <strong>Human Observational</strong> evidence and <strong>Predictive/Functional</strong> evidence.

Human observational evidence includes: (1) <strong>Population observations</strong> (e.g., allele frequency data) using codes such as BA1, BS1, PM2, and BS2, ranging from very strong benign to supporting pathogenic; (2) observations in <strong>unaffected individuals</strong> (BS2, BP2, BP5), supporting benign interpretations; (3) observations in <strong>affected individuals</strong>, with separate considerations for dominant (PS4, PS2/PM6) and recessive disease (PM3, PS4), which can provide supporting to very strong pathogenic evidence; (4) <strong>phenotype/locus specificity</strong> where a specific phenotype supports a gene–disease relationship (PP4); and (5) <strong>segregation evidence</strong> within families (PP1 for pathogenic support; BS4 for benign), ranging up to strong.

Predictive and functional evidence includes: <strong>computational or predicted effect</strong> evidence for variant types such as missense, splice, loss-of-function, in-frame indels, and other inferred effects (codes including PP3/BP4, PM1, PP2, BP1, PVS1, BP7, PM4/BP3, PS1/PM5). It also includes <strong>functional studies</strong> demonstrating impact or lack of impact (PS3 for pathogenic; BS3 for benign), with strengths up to very strong.

Finally, the document notes that a revision (SVCv4) is in progress, anticipated in late 2026, which will rename evidence codes to be more intuitive and adjust allowable strength ranges based on improved understanding of evidence relationships.

Keywords

ACMG/AMP variant interpretation

Richards et al. 2015 guidelines

sequence variant classification

evidence codes BA1 BS1 PM2 BS2

human observational evidence

population allele frequency evidence

segregation evidence PP1 BS4

computational prediction evidence PP3 BP4

functional studies PS3 BS3

SVCv4 revision 2026