Submissions for variant NM_004360.5(CDH1):c.1493A>C (p.Asp498Ala)

gnomAD frequency: 0.00001  dbSNP: rs876661065

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328294	SCV001365414	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-18	reviewed by expert panel	curation	The c.1493A>C (p.Asp498Ala) variant is present at <1/100,000 alleles in the European non-Finnish subpopulation of the gnomAD cohort (1/113,758 alleles; PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been seen in at least 10 individuals without DCG, SRC tumors, or LBC & whose families do not suggest HDGC (BS2; SCV000279435.9, SCV000637728.4). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: PM2_Supporting, BS2.
GeneDx	RCV000216744	SCV000279435	uncertain significance	not provided	2016-12-28	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.1493A>C at the cDNA level, p.Asp498Ala (D498A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAC>GCC). This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. CDH1 Asp498Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Aspartic Acid and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Asp498Ala occurs at a position that is conserved across species and is located in cadherin 4 of the extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDH1 Asp498Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000539949	SCV000637728	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 498 of the CDH1 protein (p.Asp498Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with CDH1-related conditions (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 234528). 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 disruptive. 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	RCV000570338	SCV000669006	likely benign	Hereditary cancer-predisposing syndrome	2022-06-06	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	RCV000570338	SCV000905068	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with alanine at codon 498 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several families affected with breast, gastric, and other cancers (PMID: 36436516), with one family specifying a lobular breast cancer prior to age 55. This variant has been identified in 1/251478 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	RCV000216744	SCV001134057	uncertain significance	not provided	2019-02-07	criteria provided, single submitter	clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000539949	SCV003926803	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2; BS2 (PMID: 30311375)
GenomeConnect - No Stomach For Cancer	RCV001175108	SCV001338685	not provided	Hereditary diffuse gastric adenocarcinoma; Breast lobular carcinoma		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-29-2018 by Lab or GTR ID Peter MacCallum Cancer Centre Pathology. GenomeConnect- No Stomach for Cancer assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.