Submissions for variant NM_004360.5(CDH1):c.268C>T (p.Arg90Trp)

dbSNP: rs730881661

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212347	SCV000210894	uncertain significance	not provided	2021-10-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of gastric cancer (Fang 2013); This variant is associated with the following publications: (PMID: 24983367, 25925381, 23555086)
Ambry Genetics	RCV000160382	SCV000213297	likely benign	Hereditary cancer-predisposing syndrome	2023-06-06	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.
Counsyl	RCV000410067	SCV000489601	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-11-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410067	SCV000760777	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the CDH1 protein (p.Arg90Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with gastric cancer (PMID: 23555086). ClinVar contains an entry for this variant (Variation ID: 182390). 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.
Color Diagnostics, LLC DBA Color Health	RCV000160382	SCV000904698	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 90 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with familial gastric cancer in the literature (PMID: 23555086). In a large breast cancer case-control study, this variant was identified in 4/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251338 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.
Myriad Genetics, Inc.	RCV000410067	SCV004020020	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.
Baylor Genetics	RCV004567204	SCV005060107	uncertain significance	Familial cancer of breast	2023-12-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212347	SCV005624912	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	The CDH1 c.268C>T (p.Arg90Trp) variant has been observed in a large scale breast cancer association study in 4 breast cancer cases and 1 reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000004 (1/251338 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.