Submissions for variant NM_004360.5(CDH1):c.1949T>C (p.Ile650Thr)

dbSNP: rs747235838

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165892	SCV000216645	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-30	criteria provided, single submitter	clinical testing	The p.I650T variant (also known as c.1949T>C), located in coding exon 13 of the CDH1 gene, results from a T to C substitution at nucleotide position 1949. The isoleucine at codon 650 is replaced by threonine, an amino acid with similar properties. This amino acid position is not 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.
GeneDx	RCV000478403	SCV000566208	uncertain significance	not provided	2023-02-24	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550538	SCV000637763	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 650 of the CDH1 protein (p.Ile650Thr). This variant is present in population databases (rs747235838, gnomAD 0.0009%). 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: 186317). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780091	SCV000917123	uncertain significance	not specified	2018-01-22	criteria provided, single submitter	clinical testing	Variant summary: The c.1949T>C (p.Ile650Thr) in CDH1 gene is a missense variant involves a mildly conserved nucleotide located within C-terminal catalytic domain. The 2/4 in silico tools used predict benign outcome for this variant, however no functional studies supporting these predictions were published at the time of evaluation. The c.1949T>C was identified in the control population dataset of gnomAD at a low frequency of 0.000004 (1/ 246136 chrs tested). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.000028, suggesting that it is not a common polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports, but is cited as VUS by multiple reputable databases/clinical laboratories. Taken together, due to lack of supportive evidence, the variant was classified as VUS, until new information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000165892	SCV001354011	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 650 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 CDH1-related disorders in the literature. This variant has been identified in 1/251368 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	RCV000478403	SCV004220810	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). The frequency of this variant in the general population, 0.000004 (1/251368 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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	RCV004567288	SCV005060150	uncertain significance	Familial cancer of breast	2023-11-02	criteria provided, single submitter	clinical testing