Figure 1: Examples of germline variants by somatic mutation (GxM) association.
Specific germline polymorphicor pathogenic variants impact which somatic events, mutational signatures, allele-specific copy number changes oraltered signaling pathway, are selected for in cancer cellsduring tumor evolution. In the figure, the outer circle shows germline variants and the inner wedges represent the associated somatic events for that specific example of a GxM association. BRCA1PVs are associated with a mutational signature characterized by small tandem duplications and deletions. MDB4PVs are associated with mutational signatures, particularly C>T substitution in CpG dinucleotides, and APOBECgermline variants are associated with the mutational signature C>T or C>G substitution within TCA and TCT motifs. TP53PVs are associated with chromothripsis. More generally, germline PVs and SNVs are associated with preferential gain of the risk/oncogenic allele and/or loss of the non-risk/tumor suppressing allele. Specific HLAhaplotypes have also been linked to higher and lower frequencies of specific pathogenic variants as they result in the immune system being more or less likely to recognize specific somatic mutations.