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Resolving pathogenicity classification for the CDH1 c.[715G>A] (p.Gly239Arg) Variant
Zarina Yelskaya1, Angela G Arnold2, Vanessa J Marcell2
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
The CDH1 c.[715G>A] variant disrupts normal gene splicing, leading to premature protein truncation. This finding classifies the variant as pathogenic for Hereditary Diffuse Gastric Cancer (HDGC) syndrome.
Area of Science:
- Genetics
- Molecular Biology
- Oncology
Background:
- Hereditary Diffuse Gastric Cancer (HDGC) is linked to CDH1 germline pathogenic variants.
- CDH1 variants increase predisposition to diffuse gastric cancer and lobular breast cancer.
Purpose of the Study:
- To classify the pathogenicity of the CDH1 c.[715G>A] missense variant.
- Investigate the splicing impact of this variant in a gastric cancer-prone family.
Main Methods:
- Splicing studies utilizing RT-PCR and cloning experiments.
- Analysis of the CDH1 c.[715G>A] variant's effect on normal splicing.
Main Results:
- The CDH1 c.[715G>A] variant activates a cryptic 3' acceptor splice site in exon 6.
- This activation leads to aberrant splicing and premature protein truncation of E-cadherin.
- The variant was confirmed to abolish normal splicing.
Conclusions:
- The CDH1 c.[715G>A] variant is pathogenic.
- This classification contributes to understanding HDGC genetic risk.
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