ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1906G>A (p.Ala636Thr)

gnomAD frequency: 0.00001  dbSNP: rs876658950
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221626 SCV000274831 likely benign Hereditary cancer-predisposing syndrome 2024-08-21 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000693174 SCV000821031 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-12-21 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 636 of the CDH1 protein (p.Ala636Thr). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231087). 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. 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 RCV000221626 SCV000905492 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-19 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 636 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251464 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000693174 SCV003926869 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing Not applicable criteria (PMID: 30311375)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV003477727 SCV004220807 uncertain significance not provided 2023-08-02 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an individual with a hereditary diffuse gastric cancer (HDGC) related phenotype (PMID: 36436516 (2023)). The frequency of this variant in the general population, 0.000087 (3/34592 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
KCCC/NGS Laboratory, Kuwait Cancer Control Center RCV004760448 SCV005373472 uncertain significance Familial cancer of breast 2024-10-09 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 636 of the CDH1 protein (p.Ala636Thr). This amino acid position is poorly conserved (PhyloP=1.96). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 231087). In addition, this alteration is predicted to be tolerated by in silico analysis. 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. Pathogenic/likely pathogenic variants in this CDH1 gene cause susceptibility to breast cancer (OMIM 114480).

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