ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1697T>C (p.Ile566Thr) (rs763292288)

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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 RCV000164574 SCV000215232 likely benign Hereditary cancer-predisposing syndrome 2020-10-02 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Invitae RCV000206172 SCV000260357 uncertain significance Hereditary diffuse gastric cancer 2020-03-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 566 of the CDH1 protein (p.Ile566Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs763292288, ExAC 0.006%). This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 185204). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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.
GeneDx RCV000218074 SCV000279925 uncertain significance not provided 2018-12-12 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1697T>C at the cDNA level, p.Ile566Thr (I566T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has been reported in an individual with triple negative breast cancer (Lovejoy 2018). CDH1 Ile566Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in Extracellular (Cadherin 4) domain (Brooks-Wilson 2004, Figuereido 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDH1 Ile566Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000206172 SCV000489592 uncertain significance Hereditary diffuse gastric cancer 2016-10-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164574 SCV000689478 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-12 criteria provided, single submitter clinical testing

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