ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.933C>G (p.Leu311=) (rs35539711)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV000206365 SCV001142218 benign Hereditary diffuse gastric cancer 2019-07-18 reviewed by expert panel curation The c.933C>G variant has an allele frequency of 0.03128 (3.1%, 781/24,968 alleles) in the African 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.
Ambry Genetics RCV000131958 SCV000187015 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV000206365 SCV000262223 benign Hereditary diffuse gastric cancer 2020-12-06 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000206365 SCV000398557 benign Hereditary diffuse gastric cancer 2018-01-12 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 RCV000131958 SCV000684496 benign Hereditary cancer-predisposing syndrome 2015-04-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000583727 SCV000806625 benign not specified 2016-10-03 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289653 SCV001477619 benign none provided 2019-10-13 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000583727 SCV000691816 benign not specified no assertion criteria provided clinical testing
True Health Diagnostics RCV000131958 SCV000787987 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356813 SCV001552079 benign Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Leu311Leu variant was identified in 3 of 622 proband chromosomes (frequency: 0.005) from individuals or families with early-onset gastric cancer and patients with invasive lobular carcinoma of the breast (Bacani 2006, Valente 2014). The variant was also identified in the following databases: dbSNP (ID: rs35539711) as “With other allele”, ClinVar (3x, as benign by Ambry Genetics and Invitae, as Likely benign by Illumina), Clinvitae (2x, by ClinVar and Invitae). The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Databases. The variant was identified in control databases in 847 of 277200 chromosomes at a frequency of 0.003056 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 776 of 24034 chromosomes (freq: 0.032). The p.Leu311Leu 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 this variant meets our laboratory's criteria to be classified as benign.

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