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Germline likely pathogenic variants in ataxia-telangiectasia-mutated gene in an Iranian family with hereditary diffuse gastric cancer without CDH1 mutation

1 Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful, Iran

Correspondence Address:
Abbas Moridnia,
Department of Genetics and Molecular Biology, School of Medicine, Dezful University of Medical Sciences, Dezful
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.JCRT_344_19

Background: Gastric cancer (GC) is the fourth common cancer in the world and the second cause of cancer-related mortality. Germline mutations in the E-cadherin gene (CDH1) are the most common cause of hereditary diffuse GC (HDGC) and explain 25%–30% of cases. In HDGC families without the pathogenic CDH1 variant, there is poor management and therapeutic strategies, and detect other genetic defects in HDGC, except CDH1 gene will be useful for further clarification of the disease mechanisms and risk-reducing strategies. Here, we reported an Iranian pedigree with familial HDGC to assess the fundamental genetic causes by whole-exome sequencing (WES). Materials and Methods: WES performed in an Iranian with a history of familial GC in whom no pathogenic variants or indels has been found in CDH1 and CTNNA1 genes with Sanger sequencing and multiplex ligation-dependent probe amplification methods. Results: Prioritizing genes associate with HDGC recognized several variants include c.2572T>C, and c.3161C>G in ataxia-telangiectasia mutated (ATM), c.1114A>C in BRCA2, and finally c.1173A>G in PIK3CA. Protein function prediction software tools reveal that c.3161C>G in ATM is likely pathogen. Conclusion: The results of this study suggested a role for the known cancer predisposition gene ATM in families with HDGC with no pathogenic variant in CDH1. Our results suggested that mutations in ATM and other genes, particularly the mutations found in this study, should be considered even in one case of positive familial status of HDGC disease. The presence of these mutations in patients with familial history raises important issues regarding genetic counseling.

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