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

European Journal of Human Genetics volume 29, pages 1103–1109 (2021)Cite this article

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A Correction to this article was published on 27 April 2021

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Abstract

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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Funding

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

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Authors and Affiliations

  1. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Zarina Yelskaya, Laura H. Tang & Liying Zhang

  2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Angela G. Arnold, Vanessa J. Marcell, Erin E. Salo-Mullen & Zsofia K. Stadler

  3. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Vivian E. Strong

  4. Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA

    Liying Zhang

Authors
  1. Zarina Yelskaya
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  2. Angela G. Arnold
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  3. Vanessa J. Marcell
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  4. Laura H. Tang
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  5. Erin E. Salo-Mullen
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  7. Zsofia K. Stadler
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  8. Liying Zhang
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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 29, 1103–1109 (2021). https://doi.org/10.1038/s41431-021-00825-w

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