Submissions for variant NM_004360.5(CDH1):c.1298A>G (p.Asp433Gly)

gnomAD frequency: 0.00007  dbSNP: rs376097289

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328215	SCV000864598	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.1298A>G (p.Asp433Gly) variant was observed at least twice in the homozygous state in individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; SCV000253407.6). This variant has also been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). 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): BP2_Strong, BS2.
Ambry Genetics	RCV000130470	SCV000185336	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.
GeneDx	RCV000858949	SCV000210912	likely benign	not provided	2021-03-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30680046)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196288	SCV000253407	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000196288	SCV000398563	benign	Hereditary diffuse gastric adenocarcinoma	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000196288	SCV000488137	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130470	SCV000684349	likely benign	Hereditary cancer-predisposing syndrome	2017-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212365	SCV000698359	benign	not specified	2019-03-25	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.1298A>G (p.Asp433Gly) results in a non-conservative amino acid change in 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 4.5e-05 in 246262 control chromosomes. The observed variant frequency is approximately 1.6 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.1298A>G has been reported in the literature in one individual with Hypodiploid ALL. This report does not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer . Co-occurrences with another pathogenic variant have been reported (CHEK2 c.319+2T>A), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories or groups have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six of them, including a FDA-approved expert panel, classifed this variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858949	SCV001134052	likely benign	not provided	2022-02-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130470	SCV002529054	likely benign	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000196288	SCV004019607	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.
Revvity Omics, Revvity	RCV000858949	SCV004235003	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212365	SCV004242725	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000858949	SCV004701668	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CDH1: BP4
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000130470	SCV005045490	likely benign	Hereditary cancer-predisposing syndrome	2024-03-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358324	SCV001554025	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Asp433Gly variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, and Zhejiang Colon Cancer Database. The variant was identified in dbSBP (ID: rs376097289) “With other allele” and ClinVar (classified as likely benign by Ambry Genetics, GeneDx, Invitae and Illumina; and as uncertain significance by Counsyl). The variant was observed in control databases in 11 of 246262 chromosomes at a frequency of 0.00005 (Genome Aggregation Consortium Feb 27, 2017). The variant was observed in the following populations: East Asian in 9 of 17248 chromosomes (freq: 0.0005), European in 1 of 111710 chromosomes (freq: 0.000009), and Other in 1 of 5486 chromosomes (freq: 0.0002), while it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Asp433 residue is not 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 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a greater than 10% 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 to a more benign role. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000858949	SCV001806844	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000858949	SCV001922762	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000858949	SCV001966243	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905230	SCV004722693	likely benign	CDH1-related disorder	2019-02-26	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).