ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1298A>G (p.Asp433Gly) (rs376097289)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000196288 SCV000864598 benign Hereditary diffuse gastric cancer 2018-11-21 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: BP2_Strong, BS2.
Ambry Genetics RCV000130470 SCV000185336 benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000212365 SCV000210912 likely benign not specified 2018-02-21 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 RCV000196288 SCV000253407 benign Hereditary diffuse gastric cancer 2020-11-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000196288 SCV000398563 benign Hereditary diffuse gastric cancer 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 cancer 2016-01-20 criteria provided, single submitter clinical testing
Color Health, Inc 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 2019-08-21 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.

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