While all patients with bilateral retinoblastoma can be presumed to have a germline RB1 pathogenic variant, this is particularly critical for patients with unilateral disease and no prior family history of retinoblastoma, since >15% of such isolated cases harbor a germline (or mosaic) pathogenic variant which alters the prognosis for future ocular tumors, secondary non-ocular tumors, and the risk of passing the trait to future offspring (lack of familial history and older age does not exclude a germline RB1 gene mutation) [55,56]. This evidence concerns the gene RB1 and retinoblastoma.