ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2413G>A (p.Asp805Asn) (rs200894246)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000123247 SCV000864617 benign Hereditary diffuse gastric cancer 2018-11-21 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: BA1.
GeneDx RCV000120505 SCV000149763 likely benign not specified 2018-02-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000123247 SCV000166553 benign Hereditary diffuse gastric cancer 2020-11-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115854 SCV000186424 benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other data supporting benign classification;Other strong data supporting benign classification
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 Health, Inc 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 likely benign not specified 2018-01-02 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.2413G>A (p.Asp805Asn) variant involves the alteration of a conserved nucleotide located in the Cadherin, cytoplasmic domain (IPR000233) (InterPro). 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). A functional study demonstrated the variant to slightly impair cell invasion suppression, display 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. This variant was found in 64/251876 control chromosomes at a frequency of 0.0002541, which is approximately 9 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this variant is likely a benign polymorphism. This variant was found 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). Clinical diagnostic laboratories provide conflicting classifications for this variant, from uncertain significance to likely benign/benign. Taken together, this variant is classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000858568 SCV001134079 likely benign not provided 2020-03-06 criteria provided, single submitter clinical testing
Mendelics RCV000123247 SCV001140153 uncertain significance Hereditary diffuse gastric cancer 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000123247 SCV001274533 likely benign Hereditary diffuse gastric cancer 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 Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000123247 SCV001439187 benign Hereditary diffuse gastric cancer 2020-09-09 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 cancer 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.

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