ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3DMed Clinical Laboratory Inc RCV000677871 SCV000804032 uncertain significance Adenocarcinoma of stomach 2017-11-29 no assertion criteria provided clinical testing
Ambry Genetics RCV000115833 SCV000186454 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
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.
Color RCV000115833 SCV000902722 likely benign Hereditary cancer-predisposing syndrome 2016-04-07 criteria provided, single submitter clinical testing
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.
Illumina Clinical Services Laboratory,Illumina RCV000013032 SCV000398558 likely benign Hereditary diffuse gastric cancer 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212359 SCV000919092 likely benign not specified 2017-11-03 criteria provided, single submitter clinical testing Variant summary: The CDH1 c.1018A>G (p.Thr340Ala) variant located in the extracellular domain involves the alteration of a non-conserved nucleotide and 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 68/277784 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.003604 (68/18866). This frequency is about 127 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. Several publications have cited the variant in affected individuals with hereditary gastric cancer, breast and/or ovarian cancer and colorectal cancer without strong evidence for pathogenicity. In contradiction to the variants pathogenicity, it was observed in unaffected individuals in the affected families. Multiple functional studies have been performed that indicate the variant to have an impact on cell aggregation, motility, cell-cell adhension, affecting downstream targets/pathways, along with conflicting findings. However, the variant has also been found to be expressed in the plasma membrane. Multiple clinical diagnostic laboratories and databases cite the variant with conflicting classifications such as "likely benign" or "uncertain significance" or "likely pathogenic." However, due to the high prevalence of controls predominantly East Asian, which many of the published affected individuals are of Asian descent and multiple unaffected individuals carrying the variant of interest in affected families, the variant of interest is classified as "likely benign," to suggest a possible associated risk factor, although case-control association studies need to be performed to confirm this assumption.
Invitae RCV000013032 SCV000260319 likely benign Hereditary diffuse gastric cancer 2017-12-09 criteria provided, single submitter clinical testing
OMIM RCV000013032 SCV000033277 pathogenic Hereditary diffuse gastric cancer 2003-03-01 no assertion criteria provided literature only

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