Submissions for variant NM_004360.5(CDH1):c.1930G>A (p.Asp644Asn)

gnomAD frequency: 0.00002  dbSNP: rs587781696

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129863	SCV000184680	likely benign	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231981	SCV000288452	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 644 of the CDH1 protein (p.Asp644Asn). This variant is present in population databases (rs587781696, gnomAD 0.008%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29470806, 30287823). ClinVar contains an entry for this variant (Variation ID: 141371). 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 tolerated. 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.
GeneDx	RCV000588229	SCV000567293	uncertain significance	not provided	2018-12-11	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1930G>A at the cDNA level, p.Asp644Asn (D644N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). In a Japanese case-control study, this variant was not reported in any breast cancer cases, but was observed in unaffected male controls (Momozawa 2018). CDH1 Asp644Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in cadherin 5 of the extracellurlar domain (Brooks-Wilson 2004, Figueiredo 2013, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Asp644Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129863	SCV000684388	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 644 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 (PMID: 29470806, 30287823) as well as in unaffected individuals (PMID: 30287823). This variant has not been reported in individuals affected with hereditary diffuse gastric cancer. This variant has been identified in 2/282804 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588229	SCV000698375	uncertain significance	not provided	2016-04-11	criteria provided, single submitter	clinical testing	Variant summary: The variant of interest causes a missense change involving a non-conserved nucleotide with 4/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121232, which does not exceed the predicted maximum expected allele frequency for a pathogenic CDH1 variant of 1/35335. The variant of interest, to our knowledge, has not been reported in affected individuals via publications. A reputable clinical laboratory cites the variant with a classification of "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Counsyl	RCV000231981	SCV000785795	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2017-11-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030613	SCV001193547	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Myriad Genetics, Inc.	RCV000231981	SCV004020016	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588229	SCV004220809	uncertain significance	not provided	2023-08-05	criteria provided, single submitter	clinical testing	In the published literature, the variant has not been reported in individuals with hereditary diffuse gastric cancer. However, it has been reported in individuals with breast cancer (PMID: 33471991 (2021), 29470806 (2018)) as well as unaffected individuals (PMID: 36243179 (2022), 30287823 (2018)). The frequency of this variant in the general population, 0.00008 (2/282804 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. 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.
Baylor Genetics	RCV004567098	SCV005060109	uncertain significance	Familial cancer of breast	2023-12-27	criteria provided, single submitter	clinical testing