ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.184G>A (p.Gly62Ser)

gnomAD frequency: 0.00003  dbSNP: rs587781898
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328212 SCV004035111 likely benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-03 reviewed by expert panel curation The NM_004360.5(CDH1):c.184G>A (p.Gly62Ser) variant has been observed in >10 individuals 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, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 04/24/2023)
Ambry Genetics RCV000130235 SCV000185076 likely benign Hereditary cancer-predisposing syndrome 2021-02-19 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000130235 SCV000266161 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000589761 SCV000279360 uncertain significance not provided 2023-05-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or colorectal cancer, and also in unaffected controls (Shirts et al., 2016; Dominguez-Valentin et al., 2018; Erdem et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 29371908, 10357799, 26845104, 32283892, 33471991, 35089076)
Invitae RCV000232399 SCV000288449 likely benign Hereditary diffuse gastric adenocarcinoma 2023-12-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000130235 SCV000684384 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 62 of the CDH1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer and colorectal cancer in the literature (PMID: 26845104, 29371908, 32283892, 33471991) but also in unaffected control individuals (PMID: 3471991). This variant has been identified in 7/282818 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855640 SCV000698373 uncertain significance not specified 2023-02-13 criteria provided, single submitter clinical testing Variant summary: CDH1 c.184G>A (p.Gly62Ser) results in a non-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 variant allele was found at a frequency of 2.4e-05 in 251428 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.184G>A has been reported in the literature in individuals affected with breast cancer, colorectal cancer, and unreported cancer type (Shirts_2016, Dominguez-Valentin_2018, Erdem_2020, Sahin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight submitters classified the variant as VUS while two classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Preventiongenetics, part of Exact Sciences RCV000589761 SCV000806646 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589761 SCV001134068 uncertain significance not provided 2023-05-16 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26845104 (2016)) and colorectal cancer (PMID: 32283892 (2020)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CDH1)). The frequency of this variant in the general population, 0.000046 (6/129132 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Illumina Laboratory Services, Illumina RCV000232399 SCV001277640 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago RCV000855640 SCV002064795 uncertain significance not specified 2020-04-21 criteria provided, single submitter clinical testing DNA sequence analysis of the CDH1 gene demonstrated a sequence change, c.184G>A, in exon 3 that results in an amino acid change, p.Gly62Ser. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP NA). The p.Gly62Ser change has been described in individuals with breast cancer (PMID: 29371908). The p.Gly62Ser change affects a highly conserved amino acid residue located in a domain of the CDH1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly62Ser substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Gly62Ser change remains unknown at this time.
Sema4, Sema4 RCV000130235 SCV002529095 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-05 criteria provided, single submitter curation
Mayo Clinic Laboratories, Mayo Clinic RCV000589761 SCV004227597 uncertain significance not provided 2022-03-22 criteria provided, single submitter clinical testing

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