Submissions for variant NM_004360.5(CDH1):c.2387G>A (p.Arg796Gln)

gnomAD frequency: 0.00004  dbSNP: rs587782549

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131762	SCV000186806	likely benign	Hereditary cancer-predisposing syndrome	2018-05-03	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	RCV000587217	SCV000278917	uncertain significance	not provided	2023-09-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28202063, 29295527, 15235021, 22850631, 32283892, 31159747)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228473	SCV000288465	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271418	SCV000698383	likely benign	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2387G>A (p.Arg796Gln) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 403358 control chromosomes. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), suggesting that the variant is benign. A recent case-control study showed that this variant was not associated with breast cancer (Dorling_2021). The following publication has been ascertained in the context of this evaluation (PMID: 33471991). Nine submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014; they reported the variant with conflicting assessments (Likely Benign n=3, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000131762	SCV000821973	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131762	SCV000903152	likely benign	Hereditary cancer-predisposing syndrome	2021-03-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587217	SCV001134078	uncertain significance	not provided	2023-12-15	criteria provided, single submitter	clinical testing	The CDH1 c.2387G>A (p.Arg796Gln) variant has been reported in the published literature in at least one reportedly healthy individual and affected individuals in large-scale breast cancer association studies (PMIDs: 30287823 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/genes/CDH1)). Additionally, the variant was identified in an individual with unspecified cancer (PMID: 36436516 (2023)). The frequency of this variant in the general population, 0.00012 (3/24956 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV000228473	SCV001140152	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587217	SCV002009855	uncertain significance	not provided	2021-11-03	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	RCV000228473	SCV003926934	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2_Supporting (PMID: 30311375)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002271418	SCV004242735	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing