Submissions for variant NM_004360.5(CDH1):c.1489G>A (p.Glu497Lys)

dbSNP: rs1567508990

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225725	SCV001398014	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-09-08	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 560365). This missense change has been observed in individual(s) with clinical features of CDH1-related conditions (PMID: 29805042). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 497 of the CDH1 protein (p.Glu497Lys).
Color Diagnostics, LLC DBA Color Health	RCV001525869	SCV001736070	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-29	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 497 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline mutation in individuals affected with hereditary cancer in the literature. 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.
Ambry Genetics	RCV001525869	SCV004086275	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The p.E497K variant (also known as c.1489G>A), located in coding exon 10 of the CDH1 gene, results from a G to A substitution at nucleotide position 1489. The glutamic acid at codon 497 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in an individual with cleft lip and/or palate (Cox LL et al. Am J Hum Genet, 2018 Jun;102:1143-1157). 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 this alteration remains unclear.
Institute of Human Genetics, University of Wuerzburg	RCV000678466	SCV000804529	uncertain significance	Breast carcinoma		no assertion criteria provided	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV001034595	SCV001197975	likely pathogenic	Cleft lip with or without cleft palate		no assertion criteria provided	research