ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.345G>A (p.Thr115=) (rs1801023)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000119168 SCV001244347 benign Hereditary diffuse gastric cancer 2019-10-22 reviewed by expert panel curation The c.345G>A variant has an allele frequency of 0.007677 (0.77%, 235/30,612 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD cohort (BA1). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BA1.
Invitae RCV000119168 SCV000153897 benign Hereditary diffuse gastric cancer 2020-12-08 criteria provided, single submitter clinical testing
GeneDx RCV000212351 SCV000167589 benign not specified 2013-11-08 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 RCV000128931 SCV000172802 benign Hereditary cancer-predisposing syndrome 2014-06-23 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.
PreventionGenetics,PreventionGenetics RCV000212351 SCV000310130 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000119168 SCV000398549 benign Hereditary diffuse gastric cancer 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Color Health, Inc RCV000128931 SCV000537393 benign Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000212351 SCV000705546 benign not specified 2017-01-19 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282489 SCV000885158 benign none provided 2020-05-05 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000212351 SCV000691813 likely benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000128931 SCV000805257 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357028 SCV001552353 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Thr115Thr variant was identified in 6 of 380 proband chromosomes (frequency: 0.016) from individuals or families with gastric cancer, other cancer types and normal individuals (Garziera 2013) and was present in 1 of 40 control chromosomes (frequency: 0.025) from healthy individuals (Berx 1997). The variant was also identified in dbSNP (ID: rs1801023) as “With other allele”, ClinVar (6x, as benign by Invitae, GeneDx, Ambry Genetics, Prevention Genetics, Color Genomics, as likely benign by Illumina), Clinvitae (3x as benign ), Zhejiang Colon Cancer Database. The variant was not identified in Cosmic, MutDB, databases. The variant was identified in control databases in 991 of 276784 (5 homozygous) chromosomes at a frequency of 0.0036 in the following populations: African in 12 of 24020 chromosomes (freq. 0.0005), other in 26 of 6460 chromosomes (freq. 0.004), Latino in 72 of 34410 chromosomes (freq. 0.002), European in 518 of 126334 chromosomes (freq. 0.0041), Ashkenazi Jewish in 109 of 10130 chromosomes (freq. 0.01), East Asian in 3 of 18868 chromosomes (freq. 0.00016), Finnish in 15 of 25784 chromosomes (freq. 0.0006), and South Asian in 236 of 30778 chromosomes (freq. 0.0076),.increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr115Thr 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 addition, 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 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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