ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2098C>A (p.Pro700Thr)

gnomAD frequency: 0.00002  dbSNP: rs878854681
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000470718 SCV000545404 uncertain significance Hereditary diffuse gastric adenocarcinoma 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 700 of the CDH1 protein (p.Pro700Thr). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 406634). 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 tolerated. 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.
Ambry Genetics RCV000569207 SCV000665090 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-01 criteria provided, single submitter clinical testing The p.P700T variant (also known as c.2098C>A), located in coding exon 13 of the CDH1 gene, results from a C to A substitution at nucleotide position 2098. The proline at codon 700 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Color Diagnostics, LLC DBA Color Health RCV000569207 SCV000914026 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821242 SCV002064740 uncertain significance not specified 2020-08-21 criteria provided, single submitter clinical testing DNA sequence analysis of the CDH1 gene demonstrated a sequence change, c.2098C>A, in exon 13 that results in an amino acid change, p.Pro700Thr. This sequence change does not appear to have been previously described in patients with CDH1-related disorders and has been described in the gnomAD database in one individual with an overall population frequency of 0.003% (dbSNP rs878854681). The p.Pro700Thr change affects a poorly conserved amino acid residue located in a domain of the CDH1 protein that is known to be functional. The p.Pro700Thr substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Pro700Thr change remains unknown at this time.
GeneDx RCV002298596 SCV002588085 uncertain significance not provided 2022-10-27 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631)
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000470718 SCV003926891 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing Not applicable criteria (PMID: 30311375)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001821242 SCV004242730 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005018761 SCV005644353 uncertain significance Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian cancer 2024-05-13 criteria provided, single submitter clinical testing

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