Submission Details

Fanconi anemia complementation group S (FANCS, OMIM:617883) is an autosomal recessive disorder characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic features. Homozygous or compound heterozygous pathogenic variants in BRCA1 have been reported to be associated with FANCS. In total, eight affected individuals with FANCS from six unrelated families were curated here. All three adult probands have breast or ovarian cancer diagnosed before age of 30 (PMID: 23269703; 25472942; 31347298). Two out of five younger probands were diagnosed with cancer: one with T-cell acute lymphoblastic leukemia at age 5 and one with neuroblastoma at age 2 (PMID:29712865). BRCA1, BRIP1, RAD51C, PALB2 have also been established as FA genes in the FA/BRCA DNA repair pathway. Multiple reports of functional assays using patients cells have consistent/similar results. For example, Sawyer SL, et al., 2015 (PMID: 25472942) indicated patient primary skin fibroblast cells showed reduced BRCA1 and Rad51 foci formation at IR induced damage sites and exhibited deficiency in DSB recognition. Rescue studies of PARP inhibition by Olaparib were also reported. In summary, BRCA1 is definitively associated with the autosomal recessive FANCS disorder. This has been demonstrated in both the research and clinical diagnostic settings and has been upheld over time.