CancerVar: Interpretation of Somatic variants by AMP/ASCO/CAP 2017 guideline

Therapeutic: FDA-approved therapies or in professional guidelines for a specific type of tumor Well-powered studies with consensus from experts in the field for a specific type of tumor FDA-approved therapies or in professional guidelines for different type of tumor Biomarkers that serve as inclusion criteria for clinical trials Show plausible therapeutic significance based on preclinical studies None

Diagnosis: In professional guidelines for a specific type of tumor Well-powered studies with consensus from experts in the field for a specific type of tumor Based on the results of multiple small studies May assist disease diagnosis themselves or along with other biomarkers based on small studies or a few case reports None

Prognosis: In professional guidelines for a specific type of tumor Well-powered studies with consensus from experts in the field for a specific type of tumor Based on the results of multiple small studies May assist disease diagnosis themselves or along with other biomarkers based on small studies or a few case reports None

Mutation type: Activating LOF(missense, nonsense, indel, splicing) CNVs fusions In-frame indels Functionally unknown Mostly missense Less commonly, other types Functionally Benign

Variant frequencies: Mostly mosaic Mosaic Nonmosaic Mostly nonmosaic (VAF, approximately 50% or 100%)

Potential germline: Mostly nonmosaic (VAF approximately 50% or 100%)

Population database: ESP, dbSNP, 1000Genome, ExAC: Absent Extremely low MAF MAF >=1% in the general population High MAF in some ethnic populations

Germline database: HGMD, ClinVar: May or may not be present Absent or downgraded from pathogenic to VUS Absent or present but downgraded to benign/likely benign

Somatic database: COSMIC, My Cancer Genome, TCGA: Most likely present Likely present Absent or present without association to specific tumors (potential germline VUS) Present but in very few cases Absent or present without association to specific tumors (potential rare germline polymorphism)

Predictive software: SIFT, PolyPhen2, MutTaster, CADD: Mostly damaging; information to be used for reference only Variable; information to be used for reference only Mostly benign; information to be used for reference only

Pathway involvement: Disease-associated pathways Involve disease-associated pathways or pathogenic pathways May or may not involve disease-associated pathways

Publications: functional study, population study, other: Reported evidence with consensus for Therapeutic/Diagnostic/Prognostic Multiple lines of reported evidence without consensus for Diagnostic/Prognostic Therapeutic: evidence of using FDA-approved therapies for different tumor types Therapeutic: phase 2 or 3 clinical trials for investigational therapies None or no convincing evidence to determine clinical/biological significance Reported evidence supportive of benign/likely benign; or none