ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.337A>G (p.Lys113Glu)

gnomAD frequency: 0.00001  dbSNP: rs876661106
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217135 SCV000279836 uncertain significance not provided 2018-04-03 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.337A>G at the cDNA level, p.Lys113Glu (K113E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant has been observed in co-occurrence with a pathogenic MSH6 variant, in one individual with endometrial cancer and a diagnosis of Lynch syndrome (Jori 2015). This variant has also been observed in at least one individual with non-syndromic orofacial cleft, with no specific information about cancer history (Vogelaar 2013). CDH1 Lys113Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). CDH1 Lys113Glu is located in the precursor sequence domain Brooks-WIlson 2004). 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 Lys113Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000463944 SCV000545463 uncertain significance Hereditary diffuse gastric adenocarcinoma 2023-08-16 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 113 of the CDH1 protein (p.Lys113Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with non-syndromic orofacial clefts (PMID: 23197654, 30661051). ClinVar contains an entry for this variant (Variation ID: 234799). 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.
Ambry Genetics RCV000572873 SCV000669001 likely benign Hereditary cancer-predisposing syndrome 2024-04-26 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.
Color Diagnostics, LLC DBA Color Health RCV000572873 SCV001340256 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-13 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 113 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with orofacial cleft (PMID: 23197654, 30661051) and in a patient with endometrial cancer that also harbored a mutation in MSH6 (c.2569_2572del, p.Asp857Phefs*10, PMID: 26517685). This variant has been identified in 1/251152 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000463944 SCV003927023 uncertain significance Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PM2; BS2_Supporting (PMID: 30311375)

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.