Submissions for variant NM_004360.5(CDH1):c.820G>A (p.Gly274Ser)

dbSNP: rs781513008

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328259	SCV001943359	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-09	reviewed by expert panel	curation	The c.820G>A (p.Gly274Ser) variant has been observed in >10 (25) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000760786.3, SCV000216659.5 and SCV000520889.4). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer or lobular breast cancer (BP2_Strong; SCV000520889.4). The c.820G>A variant has an allele frequency of 0.001037 (0.1037%, 5/4822 alleles) in the South Asian subpopulation of the gnomAD v.3.1 cohort (BS1). In summary, the clinical significance of this variant is benign, ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_Strong, BS1.
Ambry Genetics	RCV000165904	SCV000216659	likely benign	Hereditary cancer-predisposing syndrome	2019-03-16	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.
GeneDx	RCV001704207	SCV000520889	likely benign	not provided	2018-03-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26182300, 24204729, 25388006, 23431106, 22543498, 28873162)
Invitae	RCV000639216	SCV000760786	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 274 of the CDH1 protein (p.Gly274Ser). This variant is present in population databases (rs781513008, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with sporadic gastric cancer (PMID: 22543498). ClinVar contains an entry for this variant (Variation ID: 186326). 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. Experimental studies have shown that this missense change does not substantially affect CDH1 function (PMID: 22543498, 24204729, 25388006). 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.
Mendelics	RCV000639216	SCV000839081	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165904	SCV000903312	likely benign	Hereditary cancer-predisposing syndrome	2017-11-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000425156	SCV001159912	uncertain significance	not specified	2018-09-21	criteria provided, single submitter	clinical testing	The CDH1 c.820G>A; p.Gly274Ser variant (rs781513008), has been reported in association with gastric cancer in single case report. (Garziera 2013 Clin Exp Med). However, this variant is found in the South Asian population with an allele frequency of 0.07% (22/30,782 alleles) in the Genome Aggregation Database and has been reported in ClinVar with conflicting interpretations (Variation ID: 186326). The glycine at codon 274 is highly conserved and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. Experimental studies have shown that this missense change does not impact CDH1 protein function (Sanches et al, 2015 and Garzier et al, 2013 PLoS One). Given the limited and conflicting information regarding this variant, its clinical significance is uncertain at this time.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000425156	SCV004026637	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing