Rare missense and other loss of function mutations in ETV6 cause thrombocytopenia 5, an autosomal dominant familial disease characterized by variable thrombocytopenia (blood platelet counts from 5% to 90% of normal), mild to modest bleeding tendencies, and bone marrow biopsy findings of abnormal appearing megakaryocytes (i.e. nuclei with fewer than the normal number of lobulations) and red cell macrocytosis. Thrombocytopenia 5 is associated with an increased incidence of developing hematological (e.g. chronic myelomonocytic leukemia, acute myelocytic leukemia, B cell acute lymphoblastic leukemia, mixed phenotype acute leukemia, Myelodysplastic syndrome, and multiple myeloma) and non-hematological (e.g. skin and colon) cancers as well as non-malignant diseases such as refractory anemia myopathies, and gastroesophageal reflux disease.