ClinVar

Description

The p.P799R variant (also known as c.2396C>G) is located in coding exon 15 of the CDH1 gene. This alteration results from a C to G substitution at nucleotide position 2396. The proline at codon 799 is replaced by arginine, an amino acid with dissimilar properties. In one study, p.P799R was identified in 1 of 35 familial gastric cancer patients in a 41-year-old patient with a mixed adenocarcinoma of the gastroesophageal junction and a family history of two maternal second degree relatives with gastric cancer, but it was not found in 50 controls. Functional studies aimed to investigate the impact of this missense change on CDH1 protein function are conflicting (Keller G et al. J Med Genet. 2004 Jun;41(6):e89; Mateus AR et al. Hum Mol Genet. 2007 Jul 1;16(13):1639-47; Mateus AR et al. Exp Cell Res. 2009 May 1;315(8):1393-402; Figueiredo J et al. Eur. J. Hum. Genet., 2013 Mar;21:301-9). Additional studies investigating the impact of this missense change on the localization and abundance of CDH1 have suggested that this alteration results in a reduction of the CDH1 protein at the cell membrane (Figueiredo J et al. Eur. J. Hum. Genet., 2013 Mar;21:301-9, Sanches JM et al. Eur. J. Hum. Genet., 2015 Aug;23:1072-9). Structural analysis of P799R exhibited higher length and angle distortions and abnormal cytoskeletal organization, suggesting the formation of very dynamic and plastic cellular interactions (Mestre T et al. Sci Rep, 2016 05;6:25101). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.