Submissions for variant NM_004360.5(CDH1):c.650C>A (p.Thr217Lys)

gnomAD frequency: 0.00001  dbSNP: rs778382252

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205264	SCV000259438	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-11-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 217 of the CDH1 protein (p.Thr217Lys). This variant is present in population databases (rs778382252, gnomAD 0.003%). 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: 219527). 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	RCV000569411	SCV000661616	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-18	criteria provided, single submitter	clinical testing	The p.T217K variant (also known as c.650C>A), located in coding exon 5 of the CDH1 gene, results from a C to A substitution at nucleotide position 650. The threonine at codon 217 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569411	SCV000906736	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with lysine at codon 217 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature, but also in control individuals (PMID: 33471991). This variant has been identified in 3/251058 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985663	SCV001134092	uncertain significance	not provided	2019-03-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000985663	SCV001770729	uncertain significance	not provided	2022-07-12	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)
Sema4, Sema4	RCV000569411	SCV002529199	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	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	RCV000205264	SCV003926670	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)