ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1018A>G (p.Thr340Ala)

gnomAD frequency: 0.00022  dbSNP: rs116093741
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328156 SCV000864608 benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-08 reviewed by expert panel curation The c.1018A>G (p.Thr340Ala) variant has an allele frequency of 0.00360 (0.36%, 68/18,866 alleles) in the East Asian 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 RCV000858947 SCV000149742 likely benign not provided 2020-11-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28389907, 22850631, 15457549, 25187893, 19268661, 12588804, 11968083, 10896919, 15235021, 21989054, 19725995, 12944922, 16501831, 25856671, 16600987, 25180051, 26072394, 27121310, 26822949, 25388006, 27582386, 28503720, 28522256, 29752822, 14500541, 28580595, 31350202, 32091409, 32426482, 32521533)
Ambry Genetics RCV000115833 SCV000186454 benign Hereditary cancer-predisposing syndrome 2020-09-21 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.
Invitae RCV000013032 SCV000260319 likely benign Hereditary diffuse gastric adenocarcinoma 2024-02-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000013032 SCV000398558 likely benign Hereditary diffuse gastric adenocarcinoma 2017-04-27 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.
Color Diagnostics, LLC DBA Color Health RCV000115833 SCV000902722 likely benign Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212359 SCV000919092 benign not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1018A>G (p.Thr340Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four 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 277884 control chromosomes, predominantly at a frequency of 0.0036 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 127 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 East Asian origin. c.1018A>G has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer all of whom were of the same ethnic composition as seen in control databases . Therefore, these reports do not provide unequivocal evidence supporting a deleterious outcome. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing experience (BRCA1 c.188T>A, p.Leu63X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments ranging from likely benign (n=2) or VUS (n=3). Most recently, the Clingen CDH1 variant curation expert panel has classified this variant as benign based solely on its allele frequency in the East Asian population (ACMG, BA1). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000858947 SCV001134046 benign not provided 2019-03-26 criteria provided, single submitter clinical testing
Mendelics RCV000013032 SCV001140140 benign Hereditary diffuse gastric adenocarcinoma 2019-05-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798002 SCV002043246 likely benign Breast and/or ovarian cancer 2021-04-23 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115833 SCV002531133 benign Hereditary cancer-predisposing syndrome 2021-02-13 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 RCV000013032 SCV003926722 benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BA1 (PMID: 30311375)
PreventionGenetics, part of Exact Sciences RCV003974819 SCV004790819 likely benign CDH1-related disorder 2019-04-12 criteria provided, single submitter 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).
OMIM RCV000013032 SCV000033277 pathogenic Hereditary diffuse gastric adenocarcinoma 2003-03-01 no assertion criteria provided literature only
3DMed Clinical Laboratory Inc RCV000677871 SCV000804032 uncertain significance Gastric adenocarcinoma 2017-11-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000858947 SCV001550777 uncertain significance not provided no assertion criteria provided clinical testing The CDH1 p.Thr340Ala variant was identified in 8 of 642 proband chromosomes (frequency: 0.01) from individuals or families with gastric and colorectal cancer and was not identified in 686 control chromosomes from healthy individuals (Kim 2000, Oliveira 2002, Zhang 2006, Chang 2016). The variant was also identified in dbSNP (ID: rs116093741) with "uncertain significance, other allele," ClinVar with conflicting interpretations (1x pathogenic: OMIM, literature only; 2x likely benign: Invitae, Illumina; 2x uncertain significance: GeneDx, Ambry Genetics), COSMIC (3x somatic status unknown: 1x alveolar soft part sarcoma, 2x carcinoma, described as a "likely passenger" mutation in a thyroid carcinoma, Sohn 2016), MutDB (MutPred very confident that the variant is disease associated), Zhejiang University Database (3x "probably pathogenic" in hereditary gastric cancer, Wang 2004, Mateus 2009, Suriano 2006). The variant was not identified in the Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 68 of 277198 chromosomes at a frequency of 0.0002; or in 68 of 18866 (freq:0.0036) East Asian individuals, increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Thr340Ala missense variant was shown by computer modelling to be located in a newly characterized E-cadherin sequence motif, likely to be involved in the stabilization of the active protein conformation (Suriano 2003). In various function studies the variant was concluded to be pathogenic conferring enhanced cell motility, disrupted cell adhesion, and loss of epithelial structure (Suriano 2003, Mateus 2009). The p.Thr340Ala residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.

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