Table 3.

Criteria for evidence of benign impact of somatic variants

Category	Evidence	Criteria	Comments/Caveats
Very strong (−8 points)	SBVS1	Minor allele frequency is >5% in Genome Aggregation Database (gnomAD) in any of 5 general continental populations: African, East Asian, European (Non-Finnish), Latino, and South Asian.	If the somatic variant is in a gene known to cause predisposition to hereditary cancer, ACMG/AMP ClinGen germline expert panel gene specific guidelines (if they exist) must be consulted to establish a cutoff that takes disease prevalence into account.
Strong (−4 points)	SBS1	Minor allele frequency is >1% in Genome Aggregation Database (gnomAD) in any of 5 general continental populations: African, East Asian, European (Non-Finnish), Latino, and South Asian.	If the somatic variant is in a gene known to cause predisposition to hereditary cancer, ACMG/AMP ClinGen germline expert panel gene specific guidelines (if they exist) must be consulted to establish a cutoff that takes disease prevalence into account.
	SBS2	Well-established in vitro or in vivo functional studies show no oncogenic effects.	NA
Supporting (−1 point)	SBP1	All utilized lines of computational evidence suggest no impact of a variant (conservation/evolutionary, splicing impact, etc.).	Because many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. Can be used only once in any evaluation of a variant.
	SBP2	A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.	NA

SBVS1: Somatic Benign Very Strong-1, SBS1: Somatic Benign Strong-1, SBS2: Somatic Benign Strong-2, SBP1: Somatic Benign Supporting-1, SBP2: Somatic Benign Supporting-2