Submissions for variant NM_004360.5(CDH1):c.1793G>A (p.Arg598Gln)

gnomAD frequency: 0.00004  dbSNP: rs780759537

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168156	SCV000218817	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 598 of the CDH1 protein (p.Arg598Gln). This variant is present in population databases (rs780759537, gnomAD 0.01%). 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: 188221). 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	RCV000216786	SCV000275296	likely benign	Hereditary cancer-predisposing syndrome	2021-04-25	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	RCV000216786	SCV000684381	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 598 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in a tumor sample from an individual with diffuse gastric cancer (PMID: 9744472, 10094558), in an individual affected with breast cancer (PMID 25186627) and in an unaffected control individual (PMID: 30287823). This variant has been identified in 7/282886 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.
GeneDx	RCV001565239	SCV001788550	uncertain significance	not provided	2023-09-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Tung et al., 2015; Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 10094558, 22788692, 9744472, 10896919, 27925203, 12647996, 30287823, 29641532, 28944238, 36063148, 25186627, 15235021, 22850631, 36243179, 36436516)
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000168156	SCV003926856	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
Baylor Genetics	RCV003462259	SCV004215646	uncertain significance	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001565239	SCV004220804	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479040	SCV004223538	uncertain significance	not specified	2023-11-08	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1793G>A (p.Arg598Gln) results in a conservative amino acid change located in the Cadherin-like (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 352614 control chromosomes (gnomAD, Momozawa_2018, Akcay_2021, Okawa_2023). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1793G>A has been reported in the literature in individuals affected with breast cancer or endometrial cancer without strong evidence of causality (Tung_2015, Tian_2019, Dorling_2021, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 30287823, 33471991, 36243179, 35534704, 31054147, 25186627). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.