ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2194C>T (p.Arg732Trp)

gnomAD frequency: 0.00001  dbSNP: rs864622198
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000203693 SCV000259664 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 732 of the CDH1 protein (p.Arg732Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.06%). This missense change has been observed in individuals with hereditary diffuse gastric cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 219662). 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 disruptive. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Counsyl RCV000203693 SCV000489009 uncertain significance Hereditary diffuse gastric adenocarcinoma 2016-08-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569039 SCV000668986 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-04 criteria provided, single submitter clinical testing The p.R732W variant (also known as c.2194C>T), located in coding exon 14 of the CDH1 gene, results from a C to T substitution at nucleotide position 2194. The arginine at codon 732 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000569039 SCV000908757 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 732 of the CDH1 protein. Splice site prediction tools suggest that this variant may activate a cryptic splice acceptor site, but this has not been demonstrated by experimental studies. This variant has been reported in an individual affected with neuroblastoma in the literature (PMID: 26580448). Another missense variant at this position is classified as Likely Pathogenic in ClinVar (Variation ID: 406663) due to the creation of a de novo splice acceptor site and aberrant splicing (PMID: 15235021, 17545690, 18442100, 26072394). This variant has been identified in 1/31374 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.
GeneDx RCV001795330 SCV002032767 uncertain significance not provided 2021-12-13 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in an individual with pediatric cancer undergoing either whole exome of genome sequencing (Zhang 2015); This variant is associated with the following publications: (PMID: 15235021, 22850631, 26580448)
MGZ Medical Genetics Center RCV002288823 SCV002580221 uncertain significance Familial cancer of breast 2022-06-03 criteria provided, single submitter clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000203693 SCV003926902 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing Not applicable criteria (PMID: 30311375)
Myriad Genetics, Inc. RCV000203693 SCV004019564 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-03 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV002288823 SCV004215740 uncertain significance Familial cancer of breast 2024-03-07 criteria provided, single submitter clinical testing

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