Submissions for variant NM_004360.5(CDH1):c.2399G>A (p.Arg800His)

gnomAD frequency: 0.00002  dbSNP: rs370345996

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328223	SCV001365448	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.2399G>A (p.Arg800His) variant has an allele frequency of 0.00003 (0.003%, 1/30,614 alleles) in the South Asian gnomAD subpopulation (http://gnomad.broadinstitute.org). The variant has been seen in >10 individuals without DCG, SRC tumors, or LBC and whose families do not suggest HDGC (BS2; PMID: 26072394, SCV000186429.5, SCV000210876.13, SCV000254822.4). The variant has been identified in the homozygous state in an individual without personal and family history of DGC, LBC, or SRC tumors (BP2_Strong; SCV000186429.5). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong.
Ambry Genetics	RCV000131445	SCV000186429	likely benign	Hereditary cancer-predisposing syndrome	2021-02-02	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	RCV000212387	SCV000210876	uncertain significance	not provided	2017-02-23	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.2399G>A at the cDNA level, p.Arg800His (R800H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been observed in at least one individual with gastric cancer (van der Post 2015). CDH1 Arg800His was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. CDH1 Arg800His occurs at a position that is conserved across species and is located in the cytoplasmic domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDH1 Arg800His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198268	SCV000254822	likely benign	Hereditary diffuse gastric adenocarcinoma	2025-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131445	SCV000684431	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 800 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with intestinal-type gastric cancer (PMID: 26072394). This variant has been identified in 4/251258 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.
Counsyl	RCV000198268	SCV000785900	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-01-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131445	SCV002529130	likely benign	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000198268	SCV003926936	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2; BP2_Strong (PMID: 30311375)
Myriad Genetics, Inc.	RCV000198268	SCV004020025	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.