ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1376T>C (p.Val459Ala)

dbSNP: rs1555516109
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000572988 SCV000669061 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-05 criteria provided, single submitter clinical testing The p.V459A variant (also known as c.1376T>C), located in coding exon 10 of the CDH1 gene, results from a T to C substitution at nucleotide position 1376. The valine at codon 459 is replaced by alanine, an amino acid with similar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Color Diagnostics, LLC DBA Color Health RCV000572988 SCV001354062 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-15 criteria provided, single submitter clinical testing
GeneDx RCV001775890 SCV002013008 uncertain significance not provided 2020-04-20 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV001858276 SCV002262126 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-08-08 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 459 of the CDH1 protein (p.Val459Ala). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 483260). 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 alanine 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.
Fulgent Genetics, Fulgent Genetics RCV005018980 SCV005644344 uncertain significance Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian cancer 2024-02-22 criteria provided, single submitter clinical testing

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