ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.214G>A (p.Asp72Asn) (rs35606263)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123243 SCV000166549 likely benign Hereditary diffuse gastric cancer 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131154 SCV000186096 likely benign Hereditary cancer-predisposing syndrome 2019-12-09 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other strong data supporting benign classification
GeneDx RCV000656818 SCV000210893 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.214G>A at the cDNA level, p.Asp72Asn (D72N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has not, to our knowledge, been published as pathogenic or benign. CDH1 Asp72Asn was observed at an allele frequency of 0.049% (17/34,418) in individuals of Latino ancestry in large population cohorts (Lek 2016). CDH1 Asp72Asn is located in the precursor sequence domain (Brooks-Wilson 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDH1 Asp72Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000123243 SCV000488289 uncertain significance Hereditary diffuse gastric cancer 2016-02-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656818 SCV000600973 likely benign not provided 2020-07-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000656818 SCV000806654 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131154 SCV000821970 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000123243 SCV000839074 uncertain significance Hereditary diffuse gastric cancer 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131154 SCV000902795 likely benign Hereditary cancer-predisposing syndrome 2015-07-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235149 SCV000919098 likely benign not specified 2018-02-26 criteria provided, single submitter clinical testing Variant summary: CDH1 c.214G>A (p.Asp72Asn) results in a conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 17.32 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 Latino origin. To our knowledge, no occurrence of c.214G>A in individuals affected with Hereditary Diffuse Gastric Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656818 SCV001550075 uncertain significance not provided no assertion criteria provided clinical testing The CDH1 p.Asp72Asn variant was not identified in 14102 proband chromosomes from individuals or families with breast cancer but was present in 4 of 22482 control chromosomes (frequency: 0.0009) from healthy individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs35606263) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and five other submitters), and LOVD 3.0 (2x as VUS). The variant was identified in control databases in 29 of 277070 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24020 chromosomes (freq: 0.0001), Latino in 17 of 34418 chromosomes (freq: 0.0005), European in 6 of 126588 chromosomes (freq: 0.00005), Ashkenazi Jewish in 3 of 10148 chromosomes (freq: 0.0003); it was not observed in the Other, East Asian, Finnish, or South Asian populations. The p.Asp72 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. This variant is classified as a variant of uncertain significance.

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