ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1571G>A (p.Arg524Gln)

gnomAD frequency: 0.00001  dbSNP: rs761180883
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216734 SCV000274712 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-13 criteria provided, single submitter clinical testing The p.R524Q variant (also known as c.1571G>A), located in coding exon 11 of the CDH1 gene, results from a G to A substitution at nucleotide position 1571. The arginine at codon 524 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was identified in an individual with a history of breast cancer (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000468047 SCV000545432 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-12-31 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 230993). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (rs761180883, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the CDH1 protein (p.Arg524Gln). 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 RCV000216734 SCV000908741 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000468047 SCV003926819 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PM2 (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV000216734 SCV004611137 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 524 of the CDH1 protein (p.Arg524Gln). This variant is present in population databases (rs761180883, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 230993). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic/likely pathogenic variants in the CDH1 gene cause Diffuse gastric and lobular breast cancer syndrome (OMIM 137215).

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