Submissions for variant NM_004360.5(CDH1):c.1223C>T (p.Ala408Val)

gnomAD frequency: 0.00011  dbSNP: rs138135866

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328166	SCV004035086	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.1223C>T (p.Ala408Val) missense variant has a frequency of 0.114% (>0.1%) in South Asians (35 of 30616 alleles) in the gnomAD v2.1.1 cohort (BS1). This variant has been observed in at least 10 (122) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000260430.7, SCV000186167.6). In summary, the clinical significance of this variant is classified as of benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2.
GeneDx	RCV000858656	SCV000149745	likely benign	not provided	2020-12-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 22152101, 26759166, 23575477, 20921021, 25980754, 26674224, 26182300, 26898890, 26911350, 25186627, 29470806, 30287823, 31159747)
Ambry Genetics	RCV000115836	SCV000186167	likely benign	Hereditary cancer-predisposing syndrome	2021-12-22	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	RCV000204585	SCV000260430	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000204585	SCV000488127	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-01-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858656	SCV000600951	benign	not provided	2023-05-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115836	SCV000684340	likely benign	Hereditary cancer-predisposing syndrome	2020-02-12	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115836	SCV000821967	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000204585	SCV000839087	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212362	SCV001363227	likely benign	not specified	2019-03-28	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1223C>T (p.Ala408Val) results in a non-conservative amino acid change located in a cadherin repeat (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 324684 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 40-folds higher than 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 South Asian origin. Though the variant, c.1223C>T, has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer, colorectal cancer, and breast cancer (Caminsky_2016, Luber_2011, Mannan_2016, Mu_2016, Ross_2013, Schrader_2010, Tung_2015, Yurgeuln_2015, Momozawa_2018), it was also found in healthy controls (Momozawa_2018). 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. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant, six times as uncertain significance, and twice as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000115836	SCV002531148	likely benign	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000204585	SCV003926756	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	Not applicable criteria (PMID: 30311375)
Myriad Genetics, Inc.	RCV000204585	SCV004020035	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212362	SCV004242724	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000212362	SCV000691818	uncertain significance	not specified		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV000204585	SCV004228954	not provided	Hereditary diffuse gastric adenocarcinoma		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-24-2018 by Lab Myriad. 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.