ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.989C>T (p.Thr330Ile)

dbSNP: rs755371143
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480528 SCV000566203 uncertain significance not provided 2018-04-19 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.989C>T at the cDNA level, p.Thr330Ile (T330I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has been identified in a lobular carcinoma in situ (LCIS) specimen, but has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism (Mastracci 2005). CDH1 Thr330Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDH1 Thr330Ile is located in the Cadherin 2 domain within the Extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether CDH1 Thr330Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000580219 SCV000684498 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580219 SCV001181279 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-22 criteria provided, single submitter clinical testing The p.T330I variant (also known as c.989C>T), located in coding exon 7 of the CDH1 gene, results from a C to T substitution at nucleotide position 989. The threonine at codon 330 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001226560 SCV001398880 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-12-03 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 330 of the CDH1 protein (p.Thr330Ile). This variant is present in population databases (rs755371143, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 418843). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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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