Submissions for variant NM_004360.5(CDH1):c.2644G>A (p.Asp882Asn)

gnomAD frequency: 0.00009  dbSNP: rs200104963

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212394	SCV000149769	uncertain significance	not provided	2024-03-27	criteria provided, single submitter	clinical testing	Reported in the literature in individuals with personal or family history of breast cancer and also in unaffected control(s) (PMID: 30306255, 30287823, 33471991, 36436516); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29338689, 15235021, 22850631, 36243179, 33471991, 30287823, 30306255, 36436516)
Ambry Genetics	RCV000115860	SCV000184064	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-03	criteria provided, single submitter	clinical testing	The p.D882N variant (also known as c.2644G>A), located in coding exon 16 of the CDH1 gene, results from a G to A substitution at nucleotide position 2644. The aspartic acid at codon 882 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in an individual with ductal carcinoma in situ diagnosed at age 29 with a family history of diffuse gastric cancer diagnosed at age 52 in a maternal cousin (Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). This alteration has also been reported in breast cancer cases, as well as in controls (Momozawa Y et al. Nat Commun, 2018 10;9:4083; Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232913	SCV000288478	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115860	SCV000689523	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 882 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with breast cancer, but also in unaffected individuals in the literature (PMID: 30287823, 30306255, 33471991). This variant has been identified in 15/282744 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.
Division of Medical Genetics, University of Washington	RCV000232913	SCV001424797	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2019-08-09	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. The p.Asp882Asn variant has an overall allele frequency of 0.00005305 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may have a deleterious effect due to its relative conservation and predicted impact on the final protein product. It is unknown at this time whether this variant increases cancer risk; therefore, we consider it to be a variant of uncertain significance (VUS).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212394	SCV001469751	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212394	SCV001714552	uncertain significance	not provided	2020-08-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465518	SCV002760871	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000232913	SCV003926975	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
PreventionGenetics, part of Exact Sciences	RCV003398713	SCV004104552	uncertain significance	CDH1-related disorder	2023-04-04	criteria provided, single submitter	clinical testing	The CDH1 c.2644G>A variant is predicted to result in the amino acid substitution p.Asp882Asn. This variant has been reported with uncertain significance in an individual with breast/ovarian cancer (Bonache et al. 2018. PubMed ID: 30306255). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68867397-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003460831	SCV004215652	uncertain significance	Familial cancer of breast	2023-09-02	criteria provided, single submitter	clinical testing