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Combining clinical and molecular characterization of CDH1: a multidisciplinary approach to reclassification of a splicing variant

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Abstract

Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30–40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9 C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient’s gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9 C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.

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Funding

DeGregorio Family Foundation Grant Award (BWK).

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    Authors and Affiliations

    1. Cancer Risk and Genetics Program, St. Luke’s University Health Network, Bethlehem, PA, USA

      Corrine Fillman, Briana Marmelstein, Monica Dillon & Joseph Lopez

    2. University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

      Arravinth Anantharajah, Rashmi Tondon & Bryson W Katona

    3. Ambry Genetics, Aliso Viejo, CA, USA

      Carolyn Horton, Candace Peterson & Terra Brannan

    4. Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, 3400 Civic Center Blvd. 751 South Pavilion, Philadelphia, PA, 19104, USA

      Bryson W Katona

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    CF, AA, BM, MD, CH, CP, JL, RT, TB, BWK wrote the main manuscript text. TB, RT, BWK prepared the figures. All authors reviewed the manuscript.

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    Correspondence to Bryson W Katona.

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    CH, CP, and TB are full time employees at Ambry Genetics. The remaining authors have no relevant financial or non-financial interests to disclose.

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    Fillman, C., Anantharajah, A., Marmelstein, B. et al. Combining clinical and molecular characterization of CDH1: a multidisciplinary approach to reclassification of a splicing variant. Familial Cancer 22, 521–526 (2023). https://doi.org/10.1007/s10689-023-00346-z

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