ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1774G>A (p.Ala592Thr) (rs35187787)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000119222 SCV000864579 benign Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.1774G>A (p.Ala592Thr) variant has an allele frequency of 0.00481 (0.48%, 609/126,710 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1.
GeneDx RCV000120499 SCV000149755 benign not specified 2017-05-22 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 RCV000119222 SCV000153966 benign Hereditary diffuse gastric cancer 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115846 SCV000212796 benign Hereditary cancer-predisposing syndrome 2014-12-17 criteria provided, single submitter clinical testing This alteration is classified as 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.
Vantari Genetics RCV000115846 SCV000267031 benign Hereditary cancer-predisposing syndrome 2015-12-17 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119222 SCV000398569 likely benign Hereditary diffuse gastric cancer 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034704 SCV000610263 likely benign not provided 2017-06-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115846 SCV000684379 likely benign Hereditary cancer-predisposing syndrome 2014-12-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120499 SCV000806643 benign not specified 2016-11-22 criteria provided, single submitter clinical testing
Mendelics RCV000119222 SCV000839090 likely benign Hereditary diffuse gastric cancer 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034704 SCV001150955 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034704 SCV000043245 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000120499 SCV000084652 not provided not specified 2013-09-19 no assertion provided reference population
Pathway Genomics RCV000119222 SCV000189916 likely benign Hereditary diffuse gastric cancer 2014-07-24 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148453 SCV000190152 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Mayo Clinic Laboratories, Mayo Clinic RCV000120499 SCV000691823 likely benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000115846 SCV000886679 benign Hereditary cancer-predisposing syndrome 2018-08-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120499 SCV001551983 benign not specified no assertion criteria provided clinical testing The CDH1 p.Ala592Thr variant was identified in 19 of 5458 proband chromosomes (frequency: 0.003) from individuals or families with gastric, breast and ovarian cancers; and was present in 8 of 1472 control chromosomes (frequency: 0.005) from healthy individuals (Garziera 2013, Huiping 2001, Salahshor 2001, Schrader 2011, Stuebs 2017, Valente 2014). The variant was also identified in dbSNP (ID: rs35187787) as “with Uncertain significance, other allele”. In addition, the variant was identified in the ClinVar and Clinvitae database (as likely benign by GeneDx, Illumina clinical Services, Centre for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Pathway Genomics, CSER, University of Washington; as benign by Invitae, Ambry Genetics, Vantari Genetics; and with uncertain significance by Biesecker Lab/Human Development Section, NIH). The variant was also listed in the Cosmic database 4x as pathogenic with a FATHMM prediction score of 0.99; in the Insight Colon Cancer Gene Variant Database 6x (frequency 0.003), and in the Zhejiang Colon Cancer Database 3x. The variant was not identified in the MutDB database. Furthermore, the variant was also listed in the 1000 Genomes Project in 6 of 5000 chromosomes (frequency: 0.001) and in the NHLBI GO Exome Sequencing Project in 54 of 8600 European American alleles and in 5 of 4396 African American alleles. The variant was identified in control databases in 893 of 277218 chromosomes (4 homozygous) at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 21 of 24028 chromosomes (freq: 0.0009), Other in 24 of 6464 chromosomes (freq: 0.004), Latino in 65 of 34420 chromosomes (freq: 0.002), European Non-Finnish in 609 of 126710 chromosomes (freq: 0.005), Ashkenazi Jewish in 30 of 10152 chromosomes (freq: 0.003), Finnish in 43 of 25794 chromosomes (freq: 0.002), and South Asian in 101 of 30782 chromosomes (freq: 0.003); while the variant was not observed in the East Asian population. In one study, the frequency (0.06, n=3) of the p.Ala592Thr variant in 50 gastric tumors is almost four-fold that in normal population, suggesting that this variant indeed contributed to the tumorigenesis in a subset of gastric tumors. The authors concluded that the p.Ala592Thr variant may increase the lifetime risk of developing gastric cancer as a low penetrance variant (Huiping 2001). However allelic association studies do not support an effect of this alteration in predisposing to breast cancer in general as the variant was seen at similar frequencies between case and control groups (Salahshor 2001). In further research the p.Ala592Thr variant was again identified in both cases and controls, suggesting an improbable effect on gastric cancer pathogenesis. (Garziera 2013). In addition functional studies also support a non-pathogenic role; the p.Ala592Thr variant shows no detectable effect on adhesion activation and behaves like wild-type E-cadherin when treated with adhesion activating reagents (Petrova 2016), and cells expressing the E-cadherin variant behave like wild-type in regards to migration and aggregation (Kreller 2004). The p.Ala592 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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