Submissions for variant NM_004360.5(CDH1):c.1568A>G (p.Tyr523Cys)

gnomAD frequency: 0.00016  dbSNP: rs553907248

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328207	SCV004035101	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-03	reviewed by expert panel	curation	The filtering allele frequency of the c.1568A>G (p.Tyr523Cys) variant in the CDH1 gene is 0.15% for Latino/Admixed American chromosomes in gnomAD (95% CI of 23/15282), which meets the allele frequency threshold defined by the ClinGen CDH1 Variant Curation Expert Panel for considering strong evidence against pathogenicity for autosomal dominant hereditary diffuse gastric cancer variants (BS1). This variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 9 individuals without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). In summary, the clinical significance of this variant is classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023)
Ambry Genetics	RCV000129330	SCV000184093	likely benign	Hereditary cancer-predisposing syndrome	2020-09-24	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.
GeneDx	RCV000587509	SCV000210916	likely benign	not provided	2020-12-11	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Hauke 2018, Dutil 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27181684, 29522266, 31780696, 32936981)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206211	SCV000261154	benign	Hereditary diffuse gastric adenocarcinoma	2025-01-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000206211	SCV000488228	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-01-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587509	SCV000600961	likely benign	not provided	2023-02-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129330	SCV000689467	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with cysteine at codon 523 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 29522266, 31780696). This variant has been identified in 9/282890 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797632	SCV000698366	likely benign	not specified	2023-04-04	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1568A>G (p.Tyr523Cys) results in a non-conservative amino acid change located in the Cadherin-like domian (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 151000 control chromosomes (gnomAD v3.1.2), predominantly at a frequency of 0.0015 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 53 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Eight ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV001797632	SCV002067628	uncertain significance	not specified	2018-11-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129330	SCV002529074	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000206211	SCV004019590	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000206211	SCV004031196	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-06-21	criteria provided, single submitter	clinical testing	The CDH1 c.1568A>G (p.Tyr523Cys) missense change has a maximum subpopulation frequency of 0.011% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). This variant is located adjacent to the acceptor splice site of intron 10, however it is not predicted to affect splicing. Canonical splice site variants affecting this acceptor site are predicted to result in an in-frame insertion with a potential rescue transcript (PMID: 36600593). This variant has been identified in BRCA1/2-negative breast cancer patients, however it is unknown if these individuals had lobular breast cancer (PMID: 29522266, 31780696). To our knowledge, this variant has not been reported in the literature in individuals with diffuse gastric and lobular breast cancer syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003935212	SCV004748152	likely benign	CDH1-related disorder	2024-01-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).