ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1865A>G (p.Asn622Ser) (rs147925149)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123241 SCV000166547 uncertain significance Hereditary diffuse gastric cancer 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 622 of the CDH1 protein (p.Asn622Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs147925149, ExAC 0.01%). This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 136062). 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, 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 RCV000131244 SCV000186201 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000286705 SCV000329232 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1865A>G at the cDNA level, p.Asn622Ser (N622S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 Asn622Ser was not observed at a significant frequency in large population cohorts (Lek 2016). This variant is located in the cadherin 5 domain (Brooks-Wilson 2004, Figueiredo 2013, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether CDH1 Asn622Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000123241 SCV000488709 uncertain significance Hereditary diffuse gastric cancer 2016-05-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000286705 SCV001134069 uncertain significance not provided 2019-06-12 criteria provided, single submitter clinical testing
Color RCV000131244 SCV001348201 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-25 criteria provided, single submitter clinical testing
Clinical Genomics Lab,St. Jude Children's Research Hospital RCV000761008 SCV000890923 uncertain significance B Lymphoblastic Leukemia/Lymphoma 2016-03-07 no assertion criteria provided clinical testing

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