Submissions for variant NM_004360.5(CDH1):c.1766A>G (p.Asn589Ser)

dbSNP: rs1367108095

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283958	SCV001469488	uncertain significance	not provided	2022-09-09	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251486 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CDH1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV001806097	SCV002051874	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 589 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 hereditary cancer in the literature. This variant has been identified in 1/251486 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.
Invitae	RCV001871652	SCV002159129	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-06-15	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 993058). This missense change has been observed in individual(s) with colon cancer (PMID: 35418818). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 589 of the CDH1 protein (p.Asn589Ser).
Ambry Genetics	RCV001806097	SCV002710624	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	The p.N589S variant (also known as c.1766A>G), located in coding exon 12 of the CDH1 gene, results from an A to G substitution at nucleotide position 1766. The asparagine at codon 589 is replaced by serine, an amino acid with highly similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also detected in a patient with colorectal cancer diagnosed at age 22 (Ercoskun P et al. Mol Syndromol, 2022 Feb;13:123-131). This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 2/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003238857	SCV003936119	uncertain significance	Familial cancer of breast	2023-07-04	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 589 of the CDH1 protein.The p.N589S variant is located in coding exon 12 of the CDH1 gene, results from an A to G substitution at nucleotide position 1766. The asparagine at codon 589 is replaced by serine, an amino acid with highly similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. To our knowledge, functional studies have not been reported for this variant. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. Therefore, it is classified as variant of uncertain significance.
GeneDx	RCV001283958	SCV004025644	uncertain significance	not provided	2023-02-09	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; Published functional studies demonstrate no aberrant splicing (Karam et al., 2019); This variant is associated with the following publications: (PMID: 15235021, 22850631, 35418818, 29522266, 33980423, 31642931)