ClinVar Miner

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

gnomAD frequency: 0.00016  dbSNP: rs553907248
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328207 SCV004035101 benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-03 reviewed by expert panel curation The filtering allele frequency of the c.1568A>G (p.Tyr523Cys) variant in the CDH1 gene is 0.15% for Latino/Admixed American chromosomes in gnomAD (95% CI of 23/15282), which meets the allele frequency threshold defined by the ClinGen CDH1 Variant Curation Expert Panel for considering strong evidence against pathogenicity for autosomal dominant hereditary diffuse gastric cancer variants (BS1). This variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 9 individuals without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023)
Ambry Genetics RCV000129330 SCV000184093 likely benign Hereditary cancer-predisposing syndrome 2020-09-24 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.
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 benign Hereditary diffuse gastric adenocarcinoma 2024-01-30 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 likely benign not provided 2023-02-06 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129330 SCV000689467 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-23 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 523 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (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 2023-04-04 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 0.00017 in 151000 control chromosomes (gnomAD v3.1.2), predominantly at a frequency of 0.0015 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 53 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 a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, two as likely benign, and one as benign. 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
Myriad Genetics, Inc. RCV000206211 SCV004019590 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-06 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000206211 SCV004031196 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-06-21 criteria provided, single submitter clinical testing The CDH1 c.1568A>G (p.Tyr523Cys) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is located adjacent to the acceptor splice site of intron 10, however it is not predicted to affect splicing. Canonical splice site variants affecting this acceptor site are predicted to result in an in-frame insertion with a potential rescue transcript (PMID: 36600593). This variant has been identified in BRCA1/2-negative breast cancer patients, however it is unknown if these individuals had lobular breast cancer (PMID: 29522266, 31780696). To our knowledge, this variant has not been reported in the literature in individuals with diffuse gastric and lobular breast cancer syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences RCV003935212 SCV004748152 likely benign CDH1-related disorder 2024-01-08 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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