Familial aggregation of Waldenström's Macroglobulinemia (WM) cases, and the clustering of B-cell lymphoproliferative disorders among first degree relatives of WM patients, has been reported. Nevertheless, the possible contribution of inherited susceptibility to familial WM remains unrevealed. We performed whole exome sequencing on germline DNA obtained from four family members where coinheritance for WM was documented in three of them, and screened additional independent 246 cases, by using gene-specific mutation sequencing. Among the shared germline variants, LAPTM5(c403t) and HCLS1(g496a) represented the most recurrent ones, present in 3/3 affected members of the index family; detected in 8% of the unrelated familial cases; and present in 0.5% of the non-familial cases and in <0.05 of a control population. LAPTM5 and HCLS1 appeared as relevant WM candidate genes that characterized familial WM individuals and were also functionally relevant to the tumor clone. These findings highlight potentially novel contributors for the genetic predisposition to familial WM and indicate that LAPTM5(c403t) and HCLS1(g496a) may represent predisposition alleles in patients with familial WM.