P775: KMT2A amplification in two adult patients with B-cell acute lymphoblastic leukemia

Treatment and Management: The parents received genetic counseling to understand the diagnosis of FA.The worsening pancytopenia is being followed, and two bone marrow G-banded chromosome studies have been performed to date, both with normal results.Outcome and Follow-Up: The diagnosis of FA has resulted in frequent monitoring for progressive bone marrow failure as well as bone marrow assessment for potential clonal chromosome abnormalities.Parental studies for the FANC variants are pending.Discussion: We have previously demonstrated the utility of CBA as a functional assay in reclassification of variants of uncertain significance (VUS) in a cohort of breast cancer patients, without clinical features of FA, shown to have one pathogenic BRCA2 (FANCD1) variant and one VUS confirmed present in trans.Negative CBA results in seven individuals resulted in reclassification of the variants to benign and led to the reclassification of those variants in 89 other individuals who underwent hereditary cancer testing, thus demonstrating the power of CBA in FANC variant classification.Functional assays, such as CBA in FA, are powerful tools to aid in accurate classification of novel variants.Conclusion: CBA is a useful functional assay for classification of uncertain FANC variants into frankly benign or pathogenic categories for individuals.This case also emphasizes the importance of performing skin fibroblast CBA when blood CBA is normal, yet there is a high suspicion for FA, to address the possibility of somatic reversion.Introduction: Fanconi anemia (FA) is a rare inherited genome instability syndrome with hallmark features of bone marrow failure, generally presenting in the first decade of life, characteristic congenital abnormalities in approximately 65% of patients, and increased risk for hematological malignancies and solid tumors.FA is caused by autosomal dominant, autosomal recessive, or X-linked recessive inheritance of pathogenic variants in any of the currently recognized 23 FANC genes in the FA/BRCA DNA repair pathway.Chromosome breakage analysis (CBA) remains the gold standard for diagnosis of FA with follow-up molecular analysis required to identify the specific pathogenic gene variants.When variants are of uncertain classification, CBA may be employed as a functional assay to aid in classification.Case Presentation: We report on a 6-year-old boy who was referred for diagnostic genetic testing due to bone marrow failure.Diagnostic Workup: A bone marrow failure panel was ordered and showed two novel variants in FANCA (p.Ser1275* and deletion of exons 11-17, NM_000135.2),classified as Likely Pathogenic.A subsequent blood CBA study using both mitomycin C-and diepoxybutane-treated cultures was normal.Follow-up breakage analysis on skin fibroblasts was positive for breakage and radial formations in both MMC-and DEB-treated cultures, suggesting somatic reversion in the blood.The positive CBA results on fibroblasts allowed the reclassification of the novel variants to Pathogenic.