ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1496T>C (p.Phe499Ser)

dbSNP: rs1555516163
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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 RCV000569748 SCV000669026 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-17 criteria provided, single submitter clinical testing The p.F499S variant (also known as c.1496T>C), located in coding exon 10 of the CDH1 gene, results from a T to C substitution at nucleotide position 1496. The phenylalanine at codon 499 is replaced by serine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. 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 RCV001040672 SCV001204260 uncertain significance Hereditary diffuse gastric adenocarcinoma 2019-07-19 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 499 of the CDH1 protein (p.Phe499Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). 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 disruptive, 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 conditions. ClinVar contains an entry for this variant (Variation ID: 483233).
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV001040672 SCV003926805 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PM2 (PMID: 30311375)

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