Submissions for variant NM_004360.5(CDH1):c.407A>G (p.Gln136Arg)

dbSNP: rs1184630483

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703074	SCV000831956	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-07-06	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 579720). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 136 of the CDH1 protein (p.Gln136Arg). 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	RCV000777317	SCV000913179	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 136 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 1/251394 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.
GeneDx	RCV001759401	SCV002005374	uncertain significance	not provided	2019-06-21	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000777317	SCV002529183	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-02	criteria provided, single submitter	curation
Ambry Genetics	RCV000777317	SCV002628224	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-11	criteria provided, single submitter	clinical testing	The p.Q136R variant (also known as c.407A>G), located in coding exon 4 of the CDH1 gene, results from an A to G substitution at nucleotide position 407. The glutamine at codon 136 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320208	SCV004024288	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing