Submissions for variant NM_004360.5(CDH1):c.2474C>T (p.Pro825Leu)

gnomAD frequency: 0.00004  dbSNP: rs587781312

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129041	SCV000172952	likely benign	Hereditary cancer-predisposing syndrome	2021-11-15	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200831	SCV000254823	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000200831	SCV000489116	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000478861	SCV000564840	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	Observed in individuals with personal or family history of breast or colorectal cancer in published literature (PMID: 28961279, 25067988, 33193653, 36436516); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28961279, 22980975, 25067988, 35008396, 33193653, 36436516, 15235021, 22850631)
Color Diagnostics, LLC DBA Color Health	RCV000129041	SCV000684437	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 825 of the CDH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with invasive lobular breast cancer with a family history of stomach cancer (PMID: 25067988), in an individual affected with cervical cancer (PMID: 28961279), and in individuals affected with colorectal cancer (PMID: 33193653, 32658311). This variant has been identified in 5/282884 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.
Fulgent Genetics, Fulgent Genetics	RCV000765309	SCV000896564	uncertain significance	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478861	SCV001134081	uncertain significance	not provided	2022-11-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/129186 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 25067988 (2014)), colorectal cancer (PMID: 33193653 (2020)), and cervical adenosarcoma (PMID: 28961279 (2017)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CDH1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264574	SCV001442797	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2474C>T (p.Pro825Leu) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) 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 1.6e-05 in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2474C>T has been reported in the literature in individuals affected with HBOC or colorectal cancer (example, Valente_2014, Sung_2017, Akcay_2021, Djursby_2020). 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, 33193653, 28961279, 25067988). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=11). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV002286408	SCV002576428	uncertain significance	Familial cancer of breast	2022-08-22	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM2_SUP, PP3
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001264574	SCV002760867	uncertain significance	not specified	2023-08-15	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	RCV000200831	SCV003926955	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2_Supporting (PMID: 30311375)
Myriad Genetics, Inc.	RCV000200831	SCV004019996	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.
Baylor Genetics	RCV002286408	SCV004215620	uncertain significance	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004783749	SCV005397405	uncertain significance	Blepharocheilodontic syndrome 1	2022-09-13	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>T) at coding nucleotide 2474 of the CDH1 gene that results in a proline to leucine amino acid change at residue 825 of cadherin 1, the CDH1-encoded protein. The Pro825 residue falls in the cytoplasmic domain which mediates cadherin 1's interaction with its binding partners necessary for cell-to-cell adhesion (PMID: 22850631). This is a previously reported variant (ClinVar) that has been observed in individuals with breast cancer, cervical cancer, and colorectal cancer (PMID: 25067988, 28961279, 33193653, 32658311). This variant is present in 5 of 282,884 alleles (0.002%) in the gnomAD control population database. Multiple bioinformatic tools predict that this C to T nucleotide substitution will not alter the splicing of this variant. The proline at this position in the protein is strongly conserved across the vertebrates examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign according to the ClinGen guidelines for interpreting CDH1 variants (PMID: 30311375, version 3.1). Therefore, we consider this a variant of uncertain significance. ACMG Criteria: BP4, PS4
Mayo Clinic Laboratories, Mayo Clinic	RCV000478861	SCV005411346	uncertain significance	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002286408	SCV004101085	uncertain significance	Familial cancer of breast	2023-11-02	no assertion criteria provided	clinical testing