ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1334A>C (p.Glu445Ala) (rs374398608)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212366 SCV000149748 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1334A>C at the cDNA level, p.Glu445Ala (E445A) at the protein level, and results in the change of a Glutamic Acid to an Alanine (GAG>GCG). This variant has been observed in an individual with a personal and family history of prostate cancer (Leongamornlert 2014). CDH1 Glu445Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within cadherin 3 of the extracellular domain (Brooks-Wilson 2004, Figueiredo 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 Glu445Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000123235 SCV000166541 uncertain significance Hereditary diffuse gastric cancer 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 445 of the CDH1 protein (p.Glu445Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs374398608, ExAC 0.001%). This variant has been observed in a family affected with prostate cancer (PMID: 24556621). ClinVar contains an entry for this variant (Variation ID: 127911). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000115839 SCV000186103 likely benign Hereditary cancer-predisposing syndrome 2020-09-28 criteria provided, single submitter clinical testing Other strong data supporting benign classification
Color Health, Inc RCV000115839 SCV000684353 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with alanine at codon 445 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual with personal or family history of prostate cancer (PMID: 24556621). This variant has been identified in 4/282852 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
True Health Diagnostics RCV000115839 SCV000787975 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-11 no assertion criteria provided clinical testing

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