Identification of a Cancer-Predisposing Germline POT1 p.Ile49Metfs7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma

• Published in: Genes 2022-03, Vol.13 (4), p.591
• Main Authors: Jajosky, Audrey N, Mitchell, Anna L, Akgul, Mahmut, Shetty, Shashirekha, Yoest, Jennifer M, Gerson, Stanton L, Sadri, Navid, Oduro, Jr, Kwadwo A
• Format: Article
• Language: English
• Subjects: Aged; B-cell lymphoma; Biopsy; Bone marrow; Brain tumors; Cancer; CD5 antigen; Chromosome 7; Chronic lymphocytic leukemia; Communication; Family medical history; Fibroblasts; Gene frequency; Genomics; Glioma; Hodgkin's lymphoma; Humans; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Lymphatic leukemia; Lymphocytes B; Lymphocytosis; Lymphoma; Lymphoma, Non-Hodgkin; Male; Melanoma; Melanoma - genetics; Mutation; Next-generation sequencing; Papillary thyroid carcinoma; Patients; Proteins; Shelterin Complex; Spleen; Telomere; Telomere-Binding Proteins - genetics; Telomeres; Thyroid; Tumors
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes13040591

Germline disruptive variants in ( ) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5 CD10 B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the variant was germline. This likely pathogenic loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic variants (i.e., autosomal dominant tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the genetic locus (7q31.33).