ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1018A>G (p.Thr340Ala) (rs116093741)

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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 RCV000013032 SCV000864608 benign Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.1018A>G (p.Thr340Ala) variant has an allele frequency of 0.00360 (0.36%, 68/18,866 alleles) in the East Asian 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 RCV000212359 SCV000149742 uncertain significance not specified 2017-05-25 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.1018A>G at the cDNA level, p.Thr340Ala (T340A) at the protein level, and results in the change of a Threonine to an Alanine (ACG>GCG). This variant has been observed in several individuals with either a personal or family history of gastric cancer; however, only a few meet established Hereditary Diffuse Gastric Cancer criteria (Oliveira 2002, Wang 2004, Zhang 2006, Choi 2014, Moreira-Nunez 2014, Park 2014, van der Post 2015). Additionally, this variant was identified in several individuals with a history of colon, breast, or ovarian cancer (Kim 2011, Chang 2016, Lhota 2016, Rummel 2017). Jang et al. (2015) identified this variant in 1/196 exomes from healthy individuals of Korean decent. While some functional studies suggest that CDH1 Thr340Ala behaves similarly to wild-type with respect to localization and migration inhibition, conflicting results have been found for effects on cell aggregation and adhesion (Suriano 2003, Mateus 2009, Figueiredo 2013, Sanches 2015, Petrova 2016),CDH1 Thr340Ala was observed at an allele frequency of 0.36% (31/8654) in individuals of East Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDH1 Thr340Ala occurs at a position that is not conserved and is located in the extracellular domain (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CDH1 Thr340Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115833 SCV000186454 benign Hereditary cancer-predisposing syndrome 2020-09-21 criteria provided, single submitter clinical testing Conflicting evidence;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Other data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000013032 SCV000260319 likely benign Hereditary diffuse gastric cancer 2020-12-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000013032 SCV000398558 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Health, Inc RCV000115833 SCV000902722 likely benign Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212359 SCV000919092 benign not specified 2019-02-25 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1018A>G (p.Thr340Ala) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 277884 control chromosomes, predominantly at a frequency of 0.0036 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 127 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1018A>G has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer all of whom were of the same ethnic composition as seen in control databases . Therefore, these reports do not provide unequivocal evidence supporting a deleterious outcome. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing experience (BRCA1 c.188T>A, p.Leu63X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments ranging from likely benign (n=2) or VUS (n=3). Most recently, the Clingen CDH1 variant curation expert panel has classified this variant as benign based solely on its allele frequency in the East Asian population (ACMG, BA1). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000858947 SCV001134046 benign not provided 2019-03-26 criteria provided, single submitter clinical testing
Mendelics RCV000013032 SCV001140140 benign Hereditary diffuse gastric cancer 2019-05-28 criteria provided, single submitter clinical testing
OMIM RCV000013032 SCV000033277 pathogenic Hereditary diffuse gastric cancer 2003-03-01 no assertion criteria provided literature only
3DMed Clinical Laboratory Inc RCV000677871 SCV000804032 uncertain significance Adenocarcinoma of stomach 2017-11-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000858947 SCV001550777 uncertain significance not provided no assertion criteria provided clinical testing The CDH1 p.Thr340Ala variant was identified in 8 of 642 proband chromosomes (frequency: 0.01) from individuals or families with gastric and colorectal cancer and was not identified in 686 control chromosomes from healthy individuals (Kim 2000, Oliveira 2002, Zhang 2006, Chang 2016). The variant was also identified in dbSNP (ID: rs116093741) with "uncertain significance, other allele," ClinVar with conflicting interpretations (1x pathogenic: OMIM, literature only; 2x likely benign: Invitae, Illumina; 2x uncertain significance: GeneDx, Ambry Genetics), COSMIC (3x somatic status unknown: 1x alveolar soft part sarcoma, 2x carcinoma, described as a "likely passenger" mutation in a thyroid carcinoma, Sohn 2016), MutDB (MutPred very confident that the variant is disease associated), Zhejiang University Database (3x "probably pathogenic" in hereditary gastric cancer, Wang 2004, Mateus 2009, Suriano 2006). The variant was not identified in the Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 68 of 277198 chromosomes at a frequency of 0.0002; or in 68 of 18866 (freq:0.0036) East Asian individuals, increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Thr340Ala missense variant was shown by computer modelling to be located in a newly characterized E-cadherin sequence motif, likely to be involved in the stabilization of the active protein conformation (Suriano 2003). In various function studies the variant was concluded to be pathogenic conferring enhanced cell motility, disrupted cell adhesion, and loss of epithelial structure (Suriano 2003, Mateus 2009). The p.Thr340Ala residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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