ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2195G>T (p.Arg732Leu)

gnomAD frequency: 0.00001  dbSNP: rs1060501244
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001046500 SCV001210405 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-10-20 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 732 of the CDH1 protein (p.Arg732Leu). This variant is present in population databases (no rsID available, 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: 843802). 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. This variant disrupts the p.Arg732 amino acid residue in CDH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15235021, 17545690, 18442100, 26072394). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Sema4, Sema4 RCV002258101 SCV002529111 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-01 criteria provided, single submitter curation
Ambry Genetics RCV002258101 SCV003996600 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-17 criteria provided, single submitter clinical testing The p.R732L variant (also known as c.2195G>T), located in coding exon 14 of the CDH1 gene, results from a G to T substitution at nucleotide position 2195. The arginine at codon 732 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is well 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.
Baylor Genetics RCV003462535 SCV004215659 uncertain significance Familial cancer of breast 2023-08-25 criteria provided, single submitter clinical testing

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