Variants were extracted from VCF files if they were within a gene specified in a comprehensive list of 83 CPGs (Table 1) and had a predicted Sequence Ontology (SO) consequence indicating a deleterious effect on protein function. The gene list used for analysis was initially composed of all genes listed in a 2014 review of CPGs1 (n = 114; gene list in Table S3) and/or those sequenced by the Illumina TCP (n = 94). Two additional more recently described CPGs, namely NTHL1 (MIM: 602656)16 and CDKN2B (MIM: 600431),17 were also included (Table S3). We subsequently reviewed and filtered the genes to produce a list that would be applicable to referrals to clinical cancer genetic services. Genes were included if deleterious variants affecting them were associated with adult-onset tumors and if neoplastic lesions were likely to be a primary presenting feature. For example, SOS1 was not included because although Noonan syndrome is associated with increased neoplasia risk, other features of the condition are likely to prompt initial referral.
Table 1 Gene List Used for Analysis (n = 83)
AIP (MIM: 605555) EGFR (MIM: 131550)a NF1 (MIM: 613113) SDHB (MIM: 185470)
ALK (MIM: 105590)a EPCAM (MIM: 185535) NF2 (MIM: 607379) SDHC (MIM: 602413)
APC (MIM: 611731) ERCC2 (MIM: 126340)b NTHL1 (MIM: 602656)b SDHD (MIM: 602690)
ATM (MIM: 607585) ERCC3 (MIM: 133510)b PALB2 (MIM: 610355) SERPINA1 (MIM: 107400)b
AXIN2 (MIM: 604025) ERCC4 (MIM: 133520)b PDGFRA (MIM: 173490)a SMAD4 (MIM: 600993)
BAP1 (MIM: 603089) ERCC5 (MIM: 133530)b PHOX2B (MIM: 603851) SMARCA4 (MIM: 603254)
BMPR1A (MIM: 601299) EXT1 (MIM: 608177) PMS2 (MIM: 600259) SMARCB1 (MIM: 601607)
BRCA1 (MIM: 113705) EXT2 (MIM: 608210) POLD1 (MIM: 174761) SMARCE1 (MIM: 603111)
BRCA2 (MIM: 600185) FH (MIM: 136850) POLE (MIM: 174762) SRY (MIM: 480000)
BRIP1 (MIM: 605882) FLCN (MIM: 607273) POLH (MIM: 603968)b STK11 (MIM: 602216)
CDC73 (MIM: 607393) GATA2 (MIM: 137295) PRKAR1A (MIM: 188830) SUFU (MIM: 607035)
CDH1 (MIM: 192090) HFE (MIM: 613609)b PTCH1 (MIM: 601309) TGFBR1 (MIM: 190181)
CDK4 (MIM:123829)a HNF1A (MIM: 142410) PTEN (MIM: 601728) TMEM127 (MIM: 613403)
CDKN1B (MIM: 600778) KIT (MIM: 164920)a RAD51C (MIM: 602774) TP53 (MIM: 191170)
CDKN2A (MIM: 600160) MAX (MIM: 154950) RAD51D (MIM: 602954) TSC1 (MIM: 605284)
CDKN2B (MIM: 600431) MEN1 (MIM: 613733) RB1 (MIM: 614041) TSC2 (MIM: 191092)
CEBPA (MIM: 116897) MET (MIM: 164860)a RET (MIM: 164761)a VHL (MIM: 608537)
CHEK2 (MIM: 604373) MLH1 (MIM: 120436) RHBDF2 (MIM: 614404)a WT1 (MIM: 607102)
CYLD (MIM: 605018) MSH2 (MIM: 609309) RUNX1 (MIM: 151385) XPA (MIM: 611153)b
DDB2 (MIM: 600811) MSH6 (MIM: 600678) SDHA (MIM: 600857) XPC (MIM: 613208)b
DICER1 (MIM: 606241) MUTYH (MIM: 604933)b SDHAF2 (MIM: 613019)
a Considered to be proto-oncogenes.
b Considered to be associated with tumor predisposition in the homozygous or compound-heterozygous state only.