ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2248G>A (p.Asp750Asn)

dbSNP: rs1567515435
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000690254 SCV000817935 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-12-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 750 of the CDH1 protein (p.Asp750Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 28688938, 36436516, 36509094). ClinVar contains an entry for this variant (Variation ID: 569585). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV001183070 SCV001348725 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-20 criteria provided, single submitter clinical testing
GeneDx RCV001592877 SCV001817026 uncertain significance not provided 2019-09-06 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in at least one family with history consistent with pathogenic variants in this gene (Hansford 2015, Mi 2017); This variant is associated with the following publications: (PMID: 26182300, 28688938)
Ambry Genetics RCV001183070 SCV002725011 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-07 criteria provided, single submitter clinical testing The p.D750N variant (also known as c.2248G>A), located in coding exon 14 of the CDH1 gene, results from a G to A substitution at nucleotide position 2248. The aspartic acid at codon 750 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in 2 different individuals with hereditary diffuse gastric cancer (HDGC) (Hansford S et al. JAMA Oncol, 2015 Apr;1:23-32; Mi EZ et al. Gastrointest. Endosc., 2018 02;87:408-418). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000690254 SCV003926908 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PS4_Supporting; PM2 (PMID: 30311375)

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