Novel germline variants in cutaneous and uveal melanoma families

High penetrance germline mutations in CDKN2A account for susceptibility in ˜40% of cutaneous melanoma (CM) families, while mutations in the CDK4, MITF, TERT, POT1, ACD and TERF2IP genes are rare, each occurring in <1–2% of CM families. Additionally, mutations in BAP1 have been associated both with CM and uveal melanoma (UM) susceptibility, as well as susceptibility to mesothelioma and a range of other cancers. BAP1 is currently the only documented high penetrance UM gene, but is responsible for susceptibility in only ˜5% of UM families. Thus the genetic mutations underlying predisposition in the majority of CM and UM families is unknown. To identify new familial melanoma genes we have used whole genome sequencing (WGS) or whole exome sequencing (WES) of multiple affected members of >176 CM and/or UM families. Each family was prescreened and shown to be wildtype for all of the known melanoma predisposition genes. WGS/WES was performed by the Wellcome Trust Sanger Institute (UK) or Macrogen (Korea) on the Illumina Hiseq 2000 or X Ten platforms. Paired‐end reads of 75 to 100 bp were generated, with mean coverage of 60 to 96X. Sequences were mapped to the UCSC human genome reference build 19 using the BWA algorithm. Nucleotide variants were detected using bcftools and SAMtools mpileup with disabled BAQ computation. Small indels were detected with pindel and annotated to dbSNP144 using ANNOVAR. Variants were filtered for stringency using quality score of >70 and alternate read counts of >2 and >20% of all reads at a given position. Novel or rare (frequency < 0.001 in the ExAC Consortium population of 60,706 individuals) protein‐changing variants that lead to premature truncation of the protein were prioritized as likely pathogenic variants. Based on their known biology several of these genes represent plausible candidates for novel familial melanoma genes. Follow‐up studies are underway to accrue additional support for some of these genes.