ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln)

gnomAD frequency: 0.00002  dbSNP: rs373364873
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586292 SCV000149741 uncertain significance not provided 2020-03-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colon cancer (Raskin 2017); This variant is associated with the following publications: (PMID: 12414534, 12532420, 29212164)
Ambry Genetics RCV000115832 SCV000185512 likely benign Hereditary cancer-predisposing syndrome 2020-09-11 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
Invitae RCV000229894 SCV000288411 likely benign Hereditary diffuse gastric adenocarcinoma 2024-01-30 criteria provided, single submitter clinical testing
Counsyl RCV000229894 SCV000488287 uncertain significance Hereditary diffuse gastric adenocarcinoma 2016-02-12 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115832 SCV000684319 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-05 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 335 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with gastric cancer (PMID: 12414534, 12532420), breast cancer (PMID: 32959997), and an individual affected with colorectal cancer (PMID: 29212164). This variant has been identified in 7/282636 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 RCV000855585 SCV000698351 uncertain significance not specified 2023-09-29 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1004G>A (p.Arg335Gln) results in a conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-05 in 395984 control chromosomes (gnomAD). The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (2.1e-05), suggesting that the variant may be benign. c.1004G>A has been reported in the literature in individuals affected with breast cancer (e.g., Momozawa_2018, Uyisenga_2020) and at least one individual with ovarian cancer (e.g., Villy_2021) and one with colorectal cancer (e.g., Raskin_2017). These reports do not provide unequivocal conclusions about association of the variant with breast cancer. Co-occurrences with pathogenic variants have been observed in our lab (RAD51C c.706-2A>G and PMS2 c.2186_2187delTC, p.Leu729GlnfsX6), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12532420, 12414534, 29212164, 30287823, 32959997, 34541275). Nine submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 8, likely benign, n = 1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics RCV000229894 SCV000839085 uncertain significance Hereditary diffuse gastric adenocarcinoma 2018-07-02 criteria provided, single submitter clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000229894 SCV003926714 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BS2_Supporting (PMID: 30311375)
Myriad Genetics, Inc. RCV000229894 SCV004020033 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-07 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000855585 SCV004026641 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586292 SCV004220771 uncertain significance not provided 2022-09-17 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.000085 (3/35426 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant was identified in a diffuse gastric cancer tissue (PMID: 12414534 (2002)) as well as in individuals affected with colorectal cancer (PMID: 29212164 (2017)) and breast cancer (PMID: 30287823 (2018), 32959997 (2020), 33471991 (2021)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.