ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1409C>T (p.Thr470Ile) (rs370864592)

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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 RCV000123236 SCV000864605 benign Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.1409C>T (p.Thr470Ile) variant was observed in trans with a known pathogenic CDH1 variant with phase confirmed (BP2_Strong; PMID: 9537325). This variant was observed in the homozygous state in at least 6 individuals without a personal and/or family history of diffuse gastric cancer, signet ring cell tumor or lobular breast cancer (BP2_Strong; internal laboratory contributors). Additionally, this 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, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BP2_Strong, BS2.
GeneDx RCV000200980 SCV000149750 likely benign not specified 2017-11-07 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 RCV000123236 SCV000166542 benign Hereditary diffuse gastric cancer 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115841 SCV000186634 benign Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance);Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Color Health, Inc RCV000115841 SCV000537443 likely benign Hereditary cancer-predisposing syndrome 2015-08-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000200980 SCV000600959 likely benign not specified 2016-12-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590637 SCV000698362 benign not provided 2017-08-16 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.1409C>T (p.Thr470Ile) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/121516 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.000347 (3/8654). This frequency is about 12 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in affected individuals in the literature, without strong evidence for causality. One publication cites the variant in a gastric cancer family who also carried a pathogenic CDH1 variant, and the authors state the variant of interest did not co-segregate with disease in this family (Garziera_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign.
Counsyl RCV000123236 SCV000786453 likely benign Hereditary diffuse gastric cancer 2018-05-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590637 SCV000888022 benign not provided 2018-04-12 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000123236 SCV000493724 uncertain significance Hereditary diffuse gastric cancer 2015-09-26 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000200980 SCV001550607 benign not specified no assertion criteria provided clinical testing The CDH1 p.Thr470Ile variant was identified in 1 of 118 proband chromosomes (frequency: 0.008) from individuals or families with Gastric Cancer (Garziera 2013) and in 1 of 276 control chromosomes for an oral cleft study (Ittiwut, 2016). This variant was observed in population databases at an overall frequency of 0.00003 (Exome Aggregation Consortium, Genome Aggregation Database). This variant was observed in the following populations: African in 3 of 24974 chromosomes (freq: 0.0001), East Asian in 3 of 19954 chromosomes (freq: 0.0002), Other in 2 of 7228 chromosomes (freq: 0.0003), Latino in 1 of 35440 chromosomes (freq: 0.00003). The variant was not observed in the Ashkenazi Jewish, European (Finnish or non-Finnish), and South Asian populations. The p.Thr470Ile variant did not segregate with diffuse gastric carcinoma in one family studied; in addition the variant co-occurred in trans with another frameshift CDH1 variant that was most likely responsible for the diffuse gastric cancers in this family (Guilford, 1998). The p.Thr470Ile variant was identified in dbSNP (ID: rs370864592) as "With other allele", ClinVar (Clinical Significance: Benign – called by ClinGen expert panel, Invitae, Quest Diagnostics and Integrated Genetics; called likely benign by GeneDx and four other submitters; called VUS by Knight Diagnostic Laboratory). The p.Thr470 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; nevertheless, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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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