ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1465C>T (p.Pro489Ser)

dbSNP: rs786202508
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165352 SCV000216077 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-24 criteria provided, single submitter clinical testing The p.P489S variant (also known as c.1465C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1465. The proline at codon 489 is replaced by serine, an amino acid with similar properties. This alteration has been reported in an individual with a family history of breast cancer (Garcia-Pelaez J et al. Lancet Oncol, 2023 Jan;24:91-106). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000707373 SCV000836467 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-07-06 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with CDH1-related conditions. 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. 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. ClinVar contains an entry for this variant (Variation ID: 185854). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 489 of the CDH1 protein (p.Pro489Ser).
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000707373 SCV003926796 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PM2 (PMID: 30311375)
Color Diagnostics, LLC DBA Color Health RCV000165352 SCV004360485 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 489 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer and family history of breast cancer (PMID: 36436516) . This variant has not been identified 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.

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