Table 7.

Tier IV: Benign/Likely Benign Variants

Evidence source/type	Available evidence
FDA-approved therapies, PG, investigational therapies	None
Mutation type	Functionally benign or unknown; mostly missense; less commonly, other types
Variant frequencies	Mostly nonmosaic (VAF, approximately 50% or 100%)
Potential germline∗	Mostly nonmosaic (VAF, approximately 50% or 100%)
Population database: ESP, dbSNP, 1000Genome, ExAC	MAF ≥ 1% in the general population; or high MAF in some ethnic populations
Germline database: HGMD, ClinVar	Absent or present but downgraded to benign/likely benign
Somatic database: COSMIC, My Cancer Genome, TCGA	Absent or present without association to specific tumors (potential rare germline polymorphism)
Predictive software: SIFT, PolyPhen2, MutTaster, CADD	Mostly benign; information to be used for reference only
Pathway involvement	May or may not involve disease-associated pathways
Publications: functional study, population study, other	Reported evidence supportive of benign/likely benign; or none

Italicized text indicates examples provided within each category; these are not comprehensive lists, and inclusion does not represent an organizational endorsement of any individual database or product.

COSMIC, Catalog of Somatic Mutations in Cancer; dbSNP, The Database of Short Genetic Variation; ExAC, Exome Aggregation Consortium; FDA, Food and Drug Administration; HGMD, Human Gene Mutation Database; MAF, minor allele frequency; PG, professional guideline; TCGA, The Cancer Genome Atlas; VAF, variant allele frequency.

^∗Confirmation on normal tissue if tested tumor only and genetic counseling should be recommended.