ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.712A>C (p.Asn238His)

gnomAD frequency: 0.00004  dbSNP: rs730881664
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160386 SCV000210902 uncertain significance not provided 2024-01-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33471991, 15235021, 22850631, 36436516)
Labcorp Genetics (formerly Invitae), Labcorp RCV000528259 SCV000637847 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-12-17 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 238 of the CDH1 protein (p.Asn238His). This variant is present in population databases (rs730881664, gnomAD 0.004%). This missense change has been observed in individual(s) with CDH1-related conditions (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 182394). 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. 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.
Ambry Genetics RCV000561727 SCV000668993 likely benign Hereditary cancer-predisposing syndrome 2021-04-19 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health RCV000561727 SCV000908722 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-21 criteria provided, single submitter clinical testing This missense variant replaces asparagine with histidine at codon 238 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/282846 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000160386 SCV002009847 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000561727 SCV002529206 likely benign Hereditary cancer-predisposing syndrome 2021-03-01 criteria provided, single submitter curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000528259 SCV003926683 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BS2_Supporting (PMID: 30311375)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160386 SCV005624917 uncertain significance not provided 2024-08-15 criteria provided, single submitter clinical testing The CDH1 c.712A>C (p.Asn238His) variant has been reported in the published literature in an individual with personal and family history of breast and ovarian cancer (PMID: 36436516 (2023)). Additionally, the variant was reported in reportedly healthy individuals (PMIDs: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CDH1)). The frequency of this variant in the general population, 0.000039 (5/129148 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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