ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.188G>A (p.Arg63Gln)

gnomAD frequency: 0.00002  dbSNP: rs587780117
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328173 SCV000864612 benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-10 reviewed by expert panel curation The c.188G>A (p.Arg63Gln) variant has an allele frequency of 0.00109 (0.11%, 6/5486 alleles) in the Other subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring 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): BS1, BS2.
GeneDx RCV000679566 SCV000149757 likely benign not provided 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115848 SCV000185341 benign Hereditary cancer-predisposing syndrome 2018-05-18 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 RCV000226241 SCV000288450 benign Hereditary diffuse gastric adenocarcinoma 2024-01-28 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003891615 SCV000806647 likely benign CDH1-related disorder 2021-02-23 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).
Color Diagnostics, LLC DBA Color Health RCV000115848 SCV000910840 likely benign Hereditary cancer-predisposing syndrome 2015-09-09 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000679566 SCV002009860 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001796964 SCV002071976 likely benign not specified 2021-11-23 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115848 SCV002529099 benign Hereditary cancer-predisposing syndrome 2021-09-18 criteria provided, single submitter curation
Institute of Human Genetics, University of Leipzig Medical Center RCV000226241 SCV003921059 likely benign Hereditary diffuse gastric adenocarcinoma 2023-02-22 criteria provided, single submitter clinical testing _x000D_ Criteria applied: BS1, BP4
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000226241 SCV001553806 uncertain significance Hereditary diffuse gastric adenocarcinoma no assertion criteria provided clinical testing The CDH1 p.Arg63Gln variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or in the Zhejiang University database. The variant was identified in dbSNP (ID: rs587780117) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx, Ambry Geneitcs, Invitae). The variant was identified in control databases in 17 of 246200 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15304 chromosomes (freq: 0.00007), Other in 6 of 5486 chromosomes (freq: 0.001), European in 3 of 111650 chromosomes (freq: 0.00003), and South Asian in 7 of 30782 chromosomes (freq: 0.0002); it was not observed in the Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Arg63 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) 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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