Table 6.

Tier III: Variants of Unknown Clinical Significance

Evidence source/type	Available evidence
FDA-approved therapies, PG, investigational therapies	Cancer genes: none Noncancer genes (apply to cancer exome/whole genome sequencing): none
Mutation type	Functionally unknown; mostly missense, in-frame indels; less commonly, other types
Variant frequencies	Mosaic or nonmosaic
Potential germline∗	Mostly nonmosaic (VAF approximately 50% or 100%)
Population database: ESP, dbSNP, 1000Genome, ExAC	Absent or extremely low MAF
Germline database: HGMD, ClinVar	Absent or downgraded from pathogenic to VUS
Somatic database: COSMIC, My Cancer Genome, TCGA	Absent or present without association to specific tumors (potential germline VUS); present but in very few cases
Predictive software: SIFT, PolyPhen2, MutTaster, CADD	Variable; information to be used for reference only
Pathway involvement	May or may not involve disease-associated pathways
Publications: functional study, population study, other	None or no convincing evidence to determine clinical/biological significance

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; indel, insertion and deletion; MAF, minor allele frequency; PG, professional guideline; TCGA, The Cancer Genome Atlas; VAF, variant allele frequency; VUS, variant of unknown clinical significance.

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