ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.324A>G (p.Arg108=) (rs116542018)

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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 RCV001079438 SCV001365450 benign Hereditary diffuse gastric cancer 2020-02-18 reviewed by expert panel curation The NM_004360.5(CDH1):c.324A>G (p.Arg108=) variant has an allele frequency of 0.00769 (0.769%, 192/24966 alleles) in the African subpopulation and one homozygote in the European (Non-Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2_Strong). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1, BP2_Strong.
GeneDx RCV000212349 SCV000167588 benign not specified 2014-01-06 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.
Ambry Genetics RCV000124174 SCV000213147 likely benign Hereditary cancer-predisposing syndrome 2014-06-17 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.
Invitae RCV001079438 SCV000252794 benign Hereditary diffuse gastric cancer 2020-11-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000212349 SCV000340103 benign not specified 2016-02-29 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000124174 SCV000679729 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000124174 SCV000684454 benign Hereditary cancer-predisposing syndrome 2015-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588054 SCV000698395 benign not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: Variant Summary: The c.324G>A (p.Arg108=) in CDH1 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 3/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.1% (126/121336 chrs tested), mainly in individuals of African descent (0.83%; 86/10384 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic CDH1 variant (0.0028%), suggesting that it is a common polymorphism. Based on the published reports, the variant of interest was found in affected individuals as well as in unaffected controls. Lastly, the variant has been reported as Benign by multiple reputable database/clinical laboratories. Taken together, the variant was classified as Benign.
PreventionGenetics,PreventionGenetics RCV000212349 SCV000806664 benign not specified 2017-06-21 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000212349 SCV000691812 likely benign not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355320 SCV001550178 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Arg108= variant was identified in 3 of 594 proband chromosomes (frequency: 0.005) from Canadian and Brazilian individuals or families with early-onset gastric cancer or nonsyndromic orofacial cleft (reportedly associated with gastric cancer), and in 6 of 1218 chromosomes (frequency: 0.005) from healthy individuals (Bacani_2006_16801346, Brito_2015_26123647, ). The variant was also identified in dbSNP (ID: rs116542018) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Invitae and EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), and likely benign by Ambry Genetics), Clinvitae (4x), Insight Colon Cancer Gene Variant Database (2x), and in control databases in 288 (1 homozygous) of 276950 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 187 of 24030 chromosomes (freq: 0.008), Other in 4 of 6462 chromosomes (freq: 0.0006), Latino in 32 of 34418 chromosomes (freq: 0.0009), European Non-Finnish in 43 (1 homozygous) of 126460 chromosomes (freq: 0.0003), East Asian in 1 of 18866 chromosomes (freq: 0.00005), European Finnish in 20 of 25792 chromosomes (freq: 0.0008), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while not observed in the Ashkenazi Jewish population. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The p.Arg108= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. 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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