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Background: RAD51C is important in DNA repair and individuals with pathogenic RAD51C variants have increased risk of hereditary breast and ovarian cancer syndrome (HBOC), an autosomal dominant genetic predisposition to early onset breast and/or ovarian cancer. Methods: Five female HBOC probands sequenced negative for moderate-and high-risk genes but shared a recurrent variant of uncertain significance in RAD51C (NM_058216.3: c.571 + 4A > G). Participant recruitment was followed by haplotype and case/control analyses, RNA splicing analysis, gene and protein expression assays, and Sanger sequencing of tumors. Results: The RAD51C c.571 + 4A > G variant segregates with HBOC, with heterozygotes sharing a 5.07 Mbp haplotype. RAD51C c.571 + 4A > G is increased ~52-fold in the Newfoundland population compared with the general Caucasian population and positive population controls share disease-associated alleles, providing evidence of a founder effect. Splicing analysis confirmed in silico predictions that RAD51C c.571 + 4A > G causes exon 3 skipping, creating an immediate premature termination codon. Gene and protein expression were significantly reduced in a RAD51C c.571 + 4G > A heterozygote compared with a wild-type relative. Sanger sequencing of tumors from two probands indicates loss-of-heterozygosity, suggesting loss of function. Conclusion: The RAD51C c.

3 Risma TB, Alward WLM. Successful long-term management of iris flocculi and miosis in a patient with a strong family history of thoracic aortic aneurysms and dissections associated with an MYH11 mutation.

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Aortoesophageal fistula (AEF) is a rarely encountered clinical outcome that is often fatal. It is most commonly a postoperative complication of vascular surgery (secondary AEF). Reported primary causes of AEF include aortic aneurysm, atherosclerosis, infection, foreign objects, achalasia with megaesophagus, gastrointestinal malignancy, and radiotherapy. Aortoesophageal fistula is often not a top diagnostic consideration for clinicians or pathologists and has the potential to be overlooked. This report describes a rare case of AEF secondary to an esophageal traction diverticulum and associated abscess that resulted in the sudden unexpected death of a 78-year-old male. Aortoesophageal fistula is an important consideration for pathologists and requires careful consideration in the postmortem setting.