ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2281G>A (p.Gly761Arg)

gnomAD frequency: 0.00001  dbSNP: rs779648243
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328352 SCV001437629 uncertain significance CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-21 reviewed by expert panel curation The c.2281G>A (p.Gly761Arg) variant has an allele frequency of 0.00006 (0.006%, 1/16,256 alleles) in the African gnomAD subpopulation (http://gnomad.broadinstitute.org). The variant has been identified in at least two families that meet HDGC clinical criteria (PS4_Moderate; internal laboratory collaborators). The variant has also been seen in three individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (internal laboratory collaborators); however, BS2 is not applied since more than 30% of reported individuals/family meet HDGC criteria. . In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PS4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp RCV000462218 SCV000545483 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-09-14 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 761 of the CDH1 protein (p.Gly761Arg). This variant is present in population databases (rs779648243, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of CDH1-related conditions and/or hereditary diffuse gastric carcinoma (PMID: 35327954, 36436516; Invitae). ClinVar contains an entry for this variant (Variation ID: 406676). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change alters CDH1 gene expression (PMID: 35327954). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000492622 SCV000580695 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-06 criteria provided, single submitter clinical testing The p.G761R variant (also known as c.2281G>A), located in coding exon 14 of the CDH1 gene, results from a G to A substitution at nucleotide position 2281. The glycine at codon 761 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in 0/7051 unselected breast cancer patients and 1/11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration was also identified in a 26 year old male diagnosed with diffuse gastric cancer (Ben Aissa-Haj J et al. Genes (Basel), 2022 Feb;13). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Counsyl RCV000462218 SCV000786163 uncertain significance Hereditary diffuse gastric adenocarcinoma 2018-03-12 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000492622 SCV000908761 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-11 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 RCV000462218 SCV003926912 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PS4_Moderate; BS2_Supporting (PMID: 30311375)
Myriad Genetics, Inc. RCV000462218 SCV004019554 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-03-03 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.
Baylor Genetics RCV003463878 SCV004215648 uncertain significance Familial cancer of breast 2024-03-24 criteria provided, single submitter clinical testing

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.