ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1033G>A (p.Val345Ile)

dbSNP: rs764532067
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574360 SCV000669047 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-05 criteria provided, single submitter clinical testing The p.V345I variant (also known as c.1033G>A), located in coding exon 8 of the CDH1 gene, results from a G to A substitution at nucleotide position 1033. The valine at codon 345 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is well 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 RCV000574360 SCV001358490 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-18 criteria provided, single submitter clinical testing This missense variant replaces valine with isoleucine at codon 345 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251480 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001222891 SCV001395013 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-13 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 483247). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (rs764532067, gnomAD 0.003%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 345 of the CDH1 protein (p.Val345Ile). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

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