Submissions for variant NM_004360.5(CDH1):c.2602C>T (p.Arg868Cys)

dbSNP: rs864622630

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205707	SCV000261452	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 868 of the CDH1 protein (p.Arg868Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CDH1-related conditions (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 220695). 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. 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	RCV000217355	SCV000273247	likely benign	Hereditary cancer-predisposing syndrome	2023-08-21	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	RCV000478079	SCV000565919	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631)
Counsyl	RCV000205707	SCV000786217	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2018-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000217355	SCV000908775	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 868 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been observed in 1/60466 cases and 5/53461 unaffected controls (PMID: 33471991). This variant has not been identified 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.
Sema4, Sema4	RCV000217355	SCV002529156	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-15	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	RCV000205707	SCV003926968	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000205707	SCV004019538	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.
CeGaT Center for Human Genetics Tuebingen	RCV000478079	SCV004140037	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	CDH1: PM2, PP3
Baylor Genetics	RCV004567479	SCV005060106	uncertain significance	Familial cancer of breast	2024-01-03	criteria provided, single submitter	clinical testing