ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys)

gnomAD frequency: 0.00003  dbSNP: rs553907248
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129330 SCV000184093 likely benign Hereditary cancer-predisposing syndrome 2020-09-24 criteria provided, single submitter clinical testing Other strong data supporting benign classification
GeneDx RCV000587509 SCV000210916 likely benign not provided 2020-12-11 criteria provided, single submitter clinical testing Observed in individuals with breast cancer (Hauke 2018, Dutil 2019); 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: 27181684, 29522266, 31780696, 32936981)
Invitae RCV000206211 SCV000261154 likely benign Hereditary diffuse gastric adenocarcinoma 2021-12-16 criteria provided, single submitter clinical testing
Counsyl RCV000206211 SCV000488228 uncertain significance Hereditary diffuse gastric adenocarcinoma 2016-01-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587509 SCV000600961 uncertain significance not provided 2020-03-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129330 SCV000689467 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 523 of the CDH1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 29522266, 31780696). This variant has been identified in 9/282890 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797632 SCV000698366 likely benign not specified 2021-11-01 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1568A>G (p.Tyr523Cys) results in a non-conservative amino acid change located in the Cadherin-like domian (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 152228 control chromosomes. The observed variant frequency is approximately 5.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1568A>G in individuals affected with Hereditary Diffuse Gastric Cancer/breast cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=3; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV001797632 SCV002067628 uncertain significance not specified 2018-11-21 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000129330 SCV002529074 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-10 criteria provided, single submitter curation

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