ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2080G>A (p.Val694Ile) (rs587780118)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115849 SCV000149758 uncertain significance not provided 2015-02-02 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.2080G>A at the cDNA level, p.Val694Ile (V694I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). This variant was reported as a somatic variation in an intestinal-type gastric cancer tumor and was predicted by the authors to not disrupt E-cadherin protein function (Lee 2014). CDH1 Val694Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. CDH1 Val694Ile occurs at a position that is conserved across species and is located within the Cadherin 5 domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CDH1 Val694Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000222804 SCV000273443 likely benign Hereditary cancer-predisposing syndrome 2017-02-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000530518 SCV000637770 uncertain significance Hereditary diffuse gastric cancer 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 694 of the CDH1 protein (p.Val694Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 127920). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color Health, Inc RCV000222804 SCV000684394 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-16 criteria provided, single submitter clinical testing

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