Suggested algorithm for identifying patients with a deleterious germline cancer predisposition variant. When a patient is diagnosed with a hematopoietic malignancy, clinical history and tumor biopsies are performed. Personal history of prior cancer (1 other hematopoietic malignancy or solid tumor, including melanoma in an individual younger than 50 years of age), diagnosis at a younger age than seen in the general population for a given cancer, or a strong family history of cancer (relative diagnosed with cancer within 2 generations of the patient) should prompt a skin biopsy and comprehensive germline testing. If tumor-only NGS identifies a known cancer-predisposition variant and the VAF is > 0.3, germline testing of the variant should follow. As additional NGS tests are performed to monitor the patient’s clinical course, persistent deleterious variants with VAF > 0.3 should prompt consideration of germline status. This is especially warranted if the deleterious variant is present in a gene associated with cancer risk. In the future, systematic collection of a skin biopsy at the time of the initial BM biopsy and culturing of fibroblasts to obtain germline DNA may become standard (dotted line). Once a deleterious germline variant is confirmed, variant/gene-specific surveillance should be followed for the patient (including a risk assessment for cancer involving organs outside the BM), genetic counseling and germline testing should be offered to appropriate family members, and potential risks should be considered if the patient were to undergo related HSCT from a family member sharing the allele. NGS, next-generation sequencing; VAF variant allele frequency. *Comprehensive testing that includes all genes and variant types that confer cancer risk is not standardized and requires careful review of testing options.