A complex clinical case and VAF of deleterious variants seen over time. A 51-year-old white man had an 8 × 10–cm mass that was determined to be diffuse large B-cell lymphoma (DLBCL). He received 6 cycles of rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP), 2 cycles of etoposide/methylprednisolone/high-dose cytarabine/cisplatin (ESHAP), and radiation to the mediastinum, ultimately achieving a complete response. At age 57, a screening prostate-specific antigen (PSA) was 12.4 ng/mL. Prostate biopsy showed a 4 + 4 = 8 Gleason score adenocarcinoma, and the patient had a prostatectomy with normalization of his PSA. At age 61 years, he was diagnosed with essential thrombocytosis, with JAK2 p.Val617Phe. He eventually progressed to AML, when a detailed family history was obtained. (A) Family history revealed numerous relatives with cancer: mother, breast cancer (55 years old); father, prostate cancer (69 years old); maternal aunt, ovarian cancer (37 years old); maternal cousin, unknown type of leukemia; paternal grandmother, uterine cancer; paternal grandfather, head and neck cancer; paternal aunt, breast cancer (70 years old); paternal cousin, brain tumor (75 years old); paternal cousin, lymphoma (70 years old); paternal cousin, unknown type of leukemia (12 years old). Molecular profiling at AML diagnosis showed a complex karyotype, including deletions of the long arms of chromosomes 5 and 7. NGS of predominantly leukemia cells from a BM biopsy showed a TP53 mutation and a deletion within BRCA1. The patient underwent induction chemotherapy, and molecular profiling at clinical remission demonstrated persistence of the BRCA1 deletion and loss of the TP53 mutation. Germline genetic testing on DNA derived from the patient’s cultured skin fibroblasts confirmed a germline BRCA1 deletion. He underwent an allogeneic HSCT using an unrelated donor, given the potential risk of the familial BRCA1 deletion, which had been found in an HLA-matched sibling. (B) The VAF of DNA alterations are plotted over time and show persistence of the germline BRCA1 deletion at a relatively high VAF prior to HSCT; the acquired clonal JAK2 and TP53 variants prior to HSCT; and an acquired TSC2 variant post-HSCT of donor origin. Lessons from this case include: (1) The patient was diagnosed with 3 cancers by the time germline testing was performed: DLBCL, prostate cancer, and AML. Genetic counseling and testing were warranted at the time of his first cancer based on his extensive family cancer history. (2) BRCA1 and BRCA2 are Fanconi anemia-like genes,³⁷  encoding proteins important for DNA repair pathways active in the BM. Individuals with BRCA pathway mutations are at increased risk for the development of hematopoietic malignancies.³⁸  In fact, cancer predisposition syndromes generally thought of as predisposing to solid tumors also increase the risk for hematopoietic malignancies, such as Lynch and Li-Fraumeni syndromes.^39,40