Submissions for variant NM_004360.5(CDH1):c.2413G>A (p.Asp805Asn)

gnomAD frequency: 0.00026  dbSNP: rs200894246

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328177	SCV000864617	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-08	reviewed by expert panel	curation	The c.2413G>A (p.Asp805Asn) variant has an allele frequency of 0.00207 (0.21%, 21/10,148 alleles) in the Ashkenazi Jewish subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1.
GeneDx	RCV000858568	SCV000149763	likely benign	not provided	2021-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 29348693, 25980754, 25862857, 24728327, 25637381, 26601054, 26845104, 26580448, 26182300, 23197654, 28135145, 28873162, 28767289)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123247	SCV000166553	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115854	SCV000186424	benign	Hereditary cancer-predisposing syndrome	2019-01-17	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000115854	SCV000266163	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115854	SCV000684433	likely benign	Hereditary cancer-predisposing syndrome	2017-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120505	SCV000917126	benign	not specified	2021-11-08	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2413G>A (p.Asp805Asn) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251938 control chromosomes. The observed variant frequency is approximately 9 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 benign. c.2413G>A has been reported in the literature in a family with gastric and diffuse gastric cancer in an unaffected patient; however the age was not provided (Hansford_2015). An additional CDH1 variant (c.2430delT) was also identified in a proband affected with DGC in this family. This variant was also observed associated with non-syndromic cleft-palate, Lynch Syndrome, pancreatic ductal adenocarcinoma, and NSCLC patients without strong evidence for causality (Vogelaar_2013, Yurgelun_2015, Yurgelun_2017, Rangachari_2015, Shindo_2017, Shirts_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA2 c.7618-1G>A), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Vogelaar_2013). The most pronounced variant effect results in slightly impaired cell invasion suppression, displaying smaller cellular aggregates than the WT and to result in reduced membranous E-cadherin expression while not affecting the expression level of CDH1. However, the clinical relevance of these functional impacts is uncertain. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a majority consensus leaning towards benign/likely benign (n=8). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120505	SCV001134079	benign	not specified	2021-07-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000123247	SCV001140153	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000123247	SCV001274533	likely benign	Hereditary diffuse gastric adenocarcinoma	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000123247	SCV001439187	benign	Hereditary diffuse gastric adenocarcinoma	2020-09-09	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798346	SCV002043271	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115854	SCV002529133	likely benign	Hereditary cancer-predisposing syndrome	2020-10-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120505	SCV002551796	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000858568	SCV002585577	benign	not provided	2022-08-01	criteria provided, single submitter	clinical testing	CDH1: BP1, BS1, BS2
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000123247	SCV003926939	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1; BS2_Suportive (PMID: 30311375)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115854	SCV004014976	likely benign	Hereditary cancer-predisposing syndrome	2023-05-03	criteria provided, single submitter	clinical testing
ITMI	RCV000120505	SCV000084658	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000123247	SCV000190153	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-08-15	no assertion criteria provided	research	Originally interpreted based on literature review PMID: 25637381. Found in a female patient having exome sequencing for an unrelated indication. No known history of diffuse gastric cancer or breast cancer.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357821	SCV001553408	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Asp805Asn variant was identified in 2 of 2886 proband chromosomes (frequency: 0.0007) from individuals or families with hereditary diffuse gastric cancer or Lynch syndrome and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014, Hansford 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs200894246) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx and Ambry Genetics; as uncertain significance by four submitters). The variant was identified in control databases in 63 of 276968 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6460 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European in 26 of 126584 chromosomes (freq: 0.0002), Ashkenazi Jewish in 21 of 10148 chromosomes (freq: 0.002), and South Asian in 1 of 30770 chromosomes (freq: 0.00003), while the variant was not observed in the African, East Asian, and Finnish, populations. One study performed in vitro functional assay (Vogelaar 2013) and found that the variant p.Asp805Asn affects E-cadherin protein function and its subcellular localization and can be considered as a pathogenic mutation however result have no additional functional work supports this claim and more over this missense variant and similar ones in this study have been found in families without a clinical phenotype suggesting that the in vitro data does not reflect the clinical impact of the variants. The p.Asp805 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000120505	SCV001807465	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000858568	SCV001919798	likely benign	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483479	SCV004228480	not provided	Familial cancer of breast; Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-08-2016 by Lab Quest Diagnostics. GenomeConnect-Invitae Patient Insights Network 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. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV003915125	SCV004730964	likely benign	CDH1-related disorder	2021-12-16	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).