Table 1 Categories of significance and evidence and examples of genes and pathways included in the various categories felt to be specific to this protocol

Medically actionable

Analytically validated assay

Highly penetrant variants in cancer-related genes associated with disorders

Certified and established clinical or practice guidelines

Clinical validity

ATM

Direct clinical utility of a diagnostic or therapeutic nature that is part of accepted clinical practice

Direct clinical utility (established guidelines with regard to prevention, diagnosis, prognostication and/or therapy)

MLH1, MSH6, MSH2 PMS2

Preventable disease due to established treatment approaches

APC

Diagnostic grade assay available in standard clinical practice

BRCA1 or BRCA2

PALB2

MUTYH

VHL

MEN1, RET

NF2

STK11

TP53

Potential clinical utility

Clinical validity

ERBB2 (HER 2/neu) amplification [29]

Scientific literature (high level of evidence)

Clinical utility not proven in current treatment setting

Defects in genes involved in homologous recombination [30]

Pre-clinical evidence

Availability of clinical trials specific to the finding

Mutations of EGFR, KIT, BRAF, BRCA1/2, PALB2, where therapeutics are potentially accessible and clinically appropriate

Clinical trial signals

Wild-type KRAS[31]

Therapeutic opportunity:

Drug repurposing

Rescuing therapeutics

Clinical trial availability

Diagnostic grade assay available

Potentially highly replicable robust single laboratory research assay

Undetermined significance

Variants that have not as yet been definitively linked to a phenotype, clinical outcome or intervention

Not applicable

These variants form the basis of future research