ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2329G>A (p.Asp777Asn)

gnomAD frequency: 0.00016  dbSNP: rs372989292
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000206674 SCV001943334 likely benign Hereditary diffuse gastric adenocarcinoma 2021-01-26 reviewed by expert panel curation The c.2329G>A (p.Asp777Asn) missense variant has a frequency of 0.0001202 (34 of 282,830) in the gnomAD v2.1.1 cohort, with a maximum non-founder allele frequency of 0.0002400 (31 of 129,162) in the non-Finnish European subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in >100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149760.14, SCV000261509.8, PMIDs: 29522266, 26534844, 26976419, 25142776, 24728327). In summary, the clinical significance of this variant is classified as Likely Benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 2): BS2.
GeneDx RCV000487740 SCV000149760 likely benign not provided 2020-06-03 criteria provided, single submitter clinical testing 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: 26182300, 11948460, 26534844, 26976419, 17545690, 19725995, 24728327, 25142776, 25759019, 17224074, 26580448, 27739435, 22098830, 28873162, 32426482)
Ambry Genetics RCV000115851 SCV000186559 likely benign Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
Invitae RCV000206674 SCV000261509 likely benign Hereditary diffuse gastric adenocarcinoma 2021-12-17 criteria provided, single submitter clinical testing
Counsyl RCV000206674 SCV000489230 uncertain significance Hereditary diffuse gastric adenocarcinoma 2016-09-07 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000487740 SCV000575057 uncertain significance not provided 2017-01-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120504 SCV000600976 uncertain significance not specified 2017-05-11 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115851 SCV000684423 likely benign Hereditary cancer-predisposing syndrome 2020-05-11 criteria provided, single submitter clinical testing
Mendelics RCV000206674 SCV000839095 uncertain significance Hereditary diffuse gastric adenocarcinoma 2018-07-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120504 SCV000917120 likely benign not specified 2019-03-08 criteria provided, single submitter clinical testing Variant summary: CDH1 c.2329G>A (p.Asp777Asn) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277184 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast and Ovarian Cancer phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2329G>A has been reported in the literature in individuals affected with cancer including breast cancer, colorectal cancer and prostate cancer (Kraus_2015, Tung_2016, Hansford_2015, Zhang_2015, Jonsson_2002). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1x likely benign, 7x VUS). Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000206674 SCV001775535 likely benign Hereditary diffuse gastric adenocarcinoma 2021-02-16 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798345 SCV002043269 uncertain significance Breast and/or ovarian cancer 2020-06-15 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000120504 SCV002066855 uncertain significance not specified 2021-02-16 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000115851 SCV002529125 likely benign Hereditary cancer-predisposing syndrome 2021-08-25 criteria provided, single submitter curation
ITMI RCV000120504 SCV000084657 not provided not specified 2013-09-19 no assertion provided reference population
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120504 SCV002551794 likely benign not specified 2021-11-16 no assertion criteria provided clinical testing

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