Table 2.

Proposed Addition to ACMG-AMP Guidelines for Variant Classification to Incorporate Molecular Phenotype with Examples from Specific Rules for Somatic MMR Gene Mutations

Benign		Pathogenic
Strong	Supporting	Supporting	Moderate	Strong	Very Strong
ACMG General Rule
variant observed in a context that has been proven to be incompatible with molecular phenotype of pathogenic variants	variant observed in the context where other findings entirely explain molecular phenotype	variant observed in tissue contributes to phenotype associated with established pathogenic variants	variant likely to explain phenotype associated with pathogenic variants	variant observed in tissue explains phenotype associated with established pathogenic variants
MMR-Specific Rule
observed multiple times as a passenger somatic mutation in MMR gene where other mutations explain MSI and IHC patterns	somatic mutation at a VAF consistent with a passenger mutation in MMR gene where MSI and IHC are explained by other mutations	one of two somatic mutations in MMR gene that together explain MSI and IHC status without observed LOH	–	somatic mutation with clear LOH in MMR gene entirely explains MSI and IHC status