Submissions for variant NM_004360.5(CDH1):c.994G>A (p.Gly332Arg)

gnomAD frequency: 0.00001  dbSNP: rs587781759

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129978	SCV000184802	uncertain significance	Hereditary cancer-predisposing syndrome	2016-06-03	criteria provided, single submitter	clinical testing	The p.G332R variant (also known as c.994G>A) is located in coding exon 7 of the CDH1 gene. This alteration results from a G to A substitution at nucleotide position 994. The glycine at codon 332 is replaced by arginine, an amino acid with dissimilar properties. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.0008% (greater than 240000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.G332R remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000129978	SCV001358489	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 332 of the CDH1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251322 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512536	SCV003502466	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 332 of the CDH1 protein (p.Gly332Arg). This variant is present in population databases (rs587781759, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141456). 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.