Table 5.

Tier II: Variants with Potential Clinical Significance

Evidence source/type	Available evidence
FDA-approved therapies, PG, investigational therapies	Therapeutic: FDA approved for different tumor type; investigational therapies with some evidence Diagnostic: not in PG but with convincing published data Prognostic: not in PG but with convincing published data
Mutation type	Activating, LOF (missense, nonsense, indel, splicing), CNVs, fusions
Variant frequencies	Mostly mosaic
Potential germline∗	Mostly nonmosaic (VAF approximately 50% or 100%)
Population database: ESP, dbSNP, 1000Genome, ExAC	Absent or extremely low MAF
Germline database: HGMD, ClinVar	May or may not be present
Somatic database: COSMIC, My Cancer Genome, TCGA	Likely present
Predictive software: SIFT, PolyPhen2, MutTaster, CADD	Mostly damaging; information to be used for reference only
Pathway involvement	Involve disease-associated pathways or pathogenic pathways
Publications: functional study, population study, other	Therapeutic: evidence of using FDA-approved therapies for different tumor types; phase 2 or 3 clinical trials for investigational therapies Diagnostic: multiple lines of reported evidence without consensus Prognostic: multiple lines of reported evidence without consensus

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.

CNV, copy number variation; 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; indel, insertion and deletion; LOF, loss of function; 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.