Submissions for variant NM_004360.5(CDH1):c.1057G>A (p.Glu353Lys)

dbSNP: rs876661091

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328296	SCV001943339	likely pathogenic	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-24	reviewed by expert panel	curation	The c.1057G>A (p.Glu353Lys) variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two families meeting HDGC clinical criteria (PS4_moderate; SCV001378233.1, SCV000580696.4). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 32133419). This variant is predicted to affect splicing by SpliceAI (Donor Gain: score = 0.54 at -3 bp) (PP3). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (v3.1): PS3, PS4_moderate, PM2_supporting, PP3.
GeneDx	RCV000216189	SCV000279501	uncertain significance	not provided	2018-08-08	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1057G>A at the cDNA level, p.Glu353Lys (E353K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. CDH1 Glu353Lys was not observed in large population cohorts (Lek 2016). This variant is located in the cadherin 2 repeat within the extracellular domain (UniProt, Brooks-Wilson 2004, Figueiredo 2013). 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 Glu353Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000492182	SCV000580696	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-08	criteria provided, single submitter	clinical testing	The p.E353K variant (also known as c.1057G>A), located in coding exon 8 of the CDH1 gene, results from a G to A substitution at nucleotide position 1057. The glutamic acid at codon 353 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in individuals whose personal and/or family histories are consistent with CDH1-associated hereditary cancer syndrome (Choi YJ et al. PLoS One, 2020 Jul;15:e0236197; Ambry internal data). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. This prediction was supported in RNA studies demonstrating abnormal splicing in the set of samples tested (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001206899	SCV001378233	pathogenic	Hereditary diffuse gastric adenocarcinoma	2022-07-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 32133419). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. ClinVar contains an entry for this variant (Variation ID: 234571). This missense change has been observed in individuals with clinical features of hereditary diffuse gastric cancer (PMID: 32133419; Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 353 of the CDH1 protein (p.Glu353Lys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000216189	SCV001470478	uncertain significance	not provided	2019-12-09	criteria provided, single submitter	clinical testing