ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.781G>A (p.Glu261Lys) (rs121964873)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475944 SCV000545476 uncertain significance Hereditary diffuse gastric cancer 2018-09-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 261 of the CDH1 protein (p.Glu261Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121964873, ExAC 0.001%). This variant has not been reported in the literature in individuals with CDH1-related disease. ClinVar contains an entry for this variant (Variation ID: 406670). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000480274 SCV000569443 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.781G>A at the cDNA level, p.Glu261Lys (E261K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in uterine cancer (Zhao 2015). CDH1 Glu261Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Glu261Lys is located within the extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether CDH1 Glu261Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000475944 SCV001135005 uncertain significance Hereditary diffuse gastric cancer 2019-12-07 criteria provided, single submitter clinical testing A heterozygous missense variation in exon 6 of the CDH1 gene that results in the amino acid substitution of Lysine for Glutamic acid at codon 261 was detected. The observed variant c.781G>A (p.Glu261Lys) is documented as variant of uncertain significance in ClinVar database. The p.Glu261Lys variant has not been reported in the 1000 Genomes and has a minor allele frequency of 0.0008% in the ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2 tool. The reference codon is conserved in primates. In summary, the variant meets our criteria to be classified as variant of unknown significance.
Color RCV001187411 SCV001354216 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-10 criteria provided, single submitter clinical testing

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