Submissions for variant NM_004360.5(CDH1):c.1319A>G (p.Lys440Arg)

gnomAD frequency: 0.00001  dbSNP: rs864622165

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206579	SCV000259530	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 440 of the CDH1 protein (p.Lys440Arg). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 219581). 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	RCV000218783	SCV000277876	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-14	criteria provided, single submitter	clinical testing	The p.K440R variant (also known as c.1319A>G), located in coding exon 9 of the CDH1 gene, results from an A to G substitution at nucleotide position 1319. The lysine at codon 440 is replaced by arginine, an amino acid with highly 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	RCV000218783	SCV000689444	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 440 of the CDH1 protein. Splice site prediction tools suggest that this variant may impact RNA splicing. 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 2/251472 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.
Counsyl	RCV000206579	SCV000785462	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-08-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001762432	SCV002008475	uncertain significance	not provided	2021-10-29	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 has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22850631, 15235021)
Myriad Genetics, Inc.	RCV000206579	SCV004019551	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-03	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	RCV004567452	SCV005060112	uncertain significance	Familial cancer of breast	2023-12-26	criteria provided, single submitter	clinical testing