ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2104G>A (p.Glu702Lys) (rs149127230)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000200454 SCV000864600 benign Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.2104G>A (p.GLu702Lys) variant has an allele frequency of 0.00158 (0.2%, 38/24,028 alleles) in the African subpopulation of the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1.
GeneDx RCV000212381 SCV000149759 likely benign not specified 2018-02-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115850 SCV000186220 benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other strong data supporting benign classification
CSER _CC_NCGL, University of Washington RCV000200454 SCV000212207 uncertain significance Hereditary diffuse gastric cancer 2015-03-11 criteria provided, single submitter research
Invitae RCV000200454 SCV000253415 likely benign Hereditary diffuse gastric cancer 2020-11-23 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212381 SCV000593913 likely benign not specified 2017-03-30 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115850 SCV000684397 likely benign Hereditary cancer-predisposing syndrome 2017-03-05 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212381 SCV000698378 benign not specified 2020-09-14 criteria provided, single submitter clinical testing Variant summary: CDH1 c.2104G>A (p.Glu702Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 282492 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 57 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 African or African-American origin. In addition, this variant was found in nine healthy older women in a reputed germline gnomic database (FLOSSIES). The variant, c.2104G>A has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (Yurgelun_2015/2017, Ghazani_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x), likely benign (5x) and benign (2x). Additionally, one expert panel (ClinGen CDH1 Variant Curation Expert Panel) cites this variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Counsyl RCV000200454 SCV000786546 likely benign Hereditary diffuse gastric cancer 2018-05-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588944 SCV000888030 benign not provided 2018-08-03 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196782 SCV001367415 uncertain significance Endometrial carcinoma 2019-10-08 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2.

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