ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1585A>C (p.Thr529Pro)

gnomAD frequency: 0.00003  dbSNP: rs776890776
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165708 SCV000216449 benign Hereditary cancer-predisposing syndrome 2024-07-11 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000691223 SCV000818972 uncertain significance Hereditary diffuse gastric adenocarcinoma 2024-12-08 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 529 of the CDH1 protein (p.Thr529Pro). This variant is present in population databases (rs776890776, gnomAD 0.02%). This missense change has been observed in individual(s) with unspecified cancer type (PMID: 28873162). ClinVar contains an entry for this variant (Variation ID: 186165). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The proline 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.
Color Diagnostics, LLC DBA Color Health RCV000165708 SCV000908742 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces threonine with proline at codon 529 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a cohort of 1040 individuals affected with advanced cancer (PMID: 28873162). This variant has been identified in 4/282886 chromosomes 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.
Sema4, Sema4 RCV000165708 SCV002529080 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-22 criteria provided, single submitter curation
GeneDx RCV002264913 SCV002546723 uncertain significance not provided 2023-07-18 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with advanced cancer (Mandelker et al., 2017); This variant is associated with the following publications: (PMID: 28873162, 15235021, 22850631)
PreventionGenetics, part of Exact Sciences RCV003407615 SCV004113392 uncertain significance CDH1-related disorder 2023-04-27 criteria provided, single submitter clinical testing The CDH1 c.1585A>C variant is predicted to result in the amino acid substitution p.Thr529Pro. This variant has been reported in an individual with advanced cancer (eTable, Mandelker et al. 2017. PubMed ID: 28873162). This variant is reported in 4 of ~283,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-68853202-A-C). It is interpreted as uncertain in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/186165/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Breakthrough Genomics, Breakthrough Genomics RCV002264913 SCV005193462 uncertain significance not provided criteria provided, single submitter not provided
Quest Diagnostics Nichols Institute San Juan Capistrano RCV002264913 SCV005624892 uncertain significance not provided 2023-10-03 criteria provided, single submitter clinical testing

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