ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1403C>T (p.Thr468Ile)

dbSNP: rs876659141
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219425 SCV000275251 uncertain significance Hereditary cancer-predisposing syndrome 2021-05-07 criteria provided, single submitter clinical testing The p.T468I variant (also known as c.1403C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1403. The threonine at codon 468 is replaced by isoleucine, an amino acid with similar properties. This variant was reported in 0/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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 RCV000800375 SCV000940087 uncertain significance Hereditary diffuse gastric adenocarcinoma 2021-05-17 criteria provided, single submitter clinical testing 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. 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. This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 231409). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 468 of the CDH1 protein (p.Thr468Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine.

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