Fanconi anemia caused by biallelic inactivation of BRCA2 can present with an atypical cancer phenotype in adulthood. Issue 1 (26th September 2022)

• Record Type: Journal Article
• Authors: Maxwell, Kara N.; Patel, Vishal; Nead, Kevin T.; Merrill, Shana; Clark, Dana; Jiang, Qinqin; Wubbenhorst, Bradley; D'Andrea, Kurt; Cohen, Roger B.; Domchek, Susan M.; Morrissette, Jennifer J. D.; Greenberg, Roger A.; Babushok, Daria V.; Nathanson, Katherine L.
• Is Part Of: Clinical genetics. Volume 103:Issue 1(2023)
• Page Start: 119
• Page End: 124
• Publication Date: 2022-09-26
• Subjects: biallelic -- BRCA2 -- FANC‐D1 -- Fanconi anemia -- whole exome sequencing; Medical genetics -- Periodicals; 616.0420
• DOI: 10.1111/cge.14231
• Languages: English
• ISSNs: 0009-9163

Abstract

Abstract: Inherited biallelic pathogenic variants (PVs) in BRCA2 cause Fanconi Anemia complementation group D1 (FA‐D1), a severe pediatric bone marrow failure and high‐risk cancer syndrome. We identified biallelic BRCA2 PVs in a young adult with multiple basal cell carcinomas, adult‐onset colorectal cancer and small cell neuroendocrine carcinoma, without bone marrow failure. No PVs were identified in any other known cancer susceptibility gene, and there was no evidence of reversion mosaicism. The proband's deceased sister had a classic FA‐D1 presentation and was shown to carry the same biallelic BRCA2 PVs. A lymphoblastoid cell line derived from the proband demonstrated hypersensitivity to DNA damaging agents, and bone marrow showed aberrant RAD51 staining. Family expansion demonstrated the presence of BRCA2 related cancers in heterozygous family members. Our data highlight the striking phenotypic differences which can be observed within FA‐D1 families and expands the clinical spectrum of FA‐D1 to include adult presentation with a constellation of solid tumors not previously thought of as characteristic of Fanconi Anemia. Early recognition of this syndrome in a family could prevent further morbidity and mortality by implementation of hereditary breast and ovarian cancer screening and treatment strategies for heterozygous family members. Abstract : We describe a pair of siblings with biallelic BRCA2 pathogenic variants and strikingly different phenotypes. As opposed to classic Fanconi Anemia D1 patients, including her sister, the proband presented with atypical Fanconi anemia cancers in adulthood, thereby expanding the phenotype associated with biallelic BRCA2 pathogenic variants.