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Resolving pathogenicity classification for the CDH1 c.[715G>A] (p.Gly239Arg) Variant



Hereditary Diffuse Gastric Cancer (HDGC) syndrome is associated with CDH1 germline likely pathogenic/pathogenic variants. Carriers of CDH1 germline likely pathogenic/pathogenic variants are predisposed to diffuse gastric cancer and lobular breast cancer. This study aims to classify the CDH1 c.[715G>A] missense variant identified in a diffuse gastric cancer prone family by performing splicing studies. RT-PCR and subsequent cloning experiments were performed to investigate whether this variant completely disrupts normal splicing. This variant preferentially abolishes normal splicing through activation of a cryptic 3′ acceptor splice site within exon 6 of CDH1, presumably leading to a premature protein truncation within first extracellular domain repeat of E-cadherin protein. Our results contributed to evidence necessary to resolve pathogenicity classification of this variant, indicating that this variant is to be classified as pathogenic.

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Fig. 1: Diffuse gastric cancer in a HDGC family with CDH1 c.[715G>A] variant.
Fig. 2: In silico tools predict CDH1 c.[715G>A] variant results in novel 3′ splice site.
Fig. 3: CDH1 c.[715G>A] mutant transcripts with novel acceptor splice site deletes 29 nucleotides from the 5′ end of exon 6.


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This study was funded by Department of Pathology, Memorial Sloan Kettering Cancer Center.

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Correspondence to Liying Zhang.

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Conflict of interest

LZ: Honoraria (Future Technology Research LLC, BGI, Illumina); Honoraria and Travel and accommodation expenses (Roche Diagnostics Asia Pacific). Family members hold leadership position and ownership interest of Decipher Medicine. ZKS: Immediate family member serves as a consultant for Allergan, Adverum Biotechnologies, Alimera Sciences, Fortress Biotech, Genentech/Roche, Novartis, Optos, Regeneron, Regenxbio, and Spark Therapeutics.

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Yelskaya, Z., Arnold, A.G., Marcell, V.J. et al. Resolving pathogenicity classification for the CDH1 c.[715G>A] (p.Gly239Arg) Variant. Eur J Hum Genet (2021).

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