ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2494G>A (p.Val832Met) (rs35572355)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115856 SCV000183955 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000148456 SCV000190155 likely pathogenic Neoplasm of stomach 2014-06-01 no assertion criteria provided research
ClinGen CDH1 Variant Curation Expert Panel RCV000013033 SCV000864595 benign Hereditary diffuse gastric cancer 2018-11-21 reviewed by expert panel curation The c.2494G>A (p.Val832Met) variant has an allele frequency of 0.00175 (0.175%, 33/18,868 alleles) in the East Asian subpopulation of the gnomAD cohort (BS1). 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: BS1, BS2.
Color RCV000115856 SCV000902855 likely benign Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing
GeneDx RCV000587650 SCV000149765 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.2494G>A at the cDNA level, p.Val832Met (V832M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). CDH1 Val832Met has been identified in individuals with diffuse gastric cancer (Yabuta 2002, Oliveira 2009) and lobular breast cancer (Schrader 2011), as well as in individuals with gastric cancer or breast cancer of unspecified pathology (Kim 2017, Rummel 2017), and in individuals not selected for cancer history undergoing exome sequencing (Dorschner 2013, Jang 2015). Mateus et al. (2009) determined that CDH1 Val832Met was comparable to wild-type in a cell motility assay, while others concluded that this variant impacted cell-cell adhesion and induced invasion (Suriano 2003a, Suriano 2003b, Pereira 2006, Figueiredo 2013, Sanches 2015). CDH1 Val832Met was observed at an allele frequency of 0.17% (33/18,868) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located within the cytoplasmic domain, region of interaction with PIPKI gamma, and the region required for binding alpha, beta, and gamma catenins (Brooks-Wilson 2004, Figueiredo 2013). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether CDH1 Val832Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000115856 SCV000821974 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000120506 SCV000084659 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000120506 SCV000698386 likely benign not specified 2019-01-07 criteria provided, single submitter clinical testing CDH1 c.2494G>A (p.Val832Met) results in a conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 60 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer (HDGC) phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.2494G>A, has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer (Yabuta_2002, Kim_2017), Breast Cancer (Schrader_2011, Rummel_2017, Siraj_2017), Lynch Syndrome (Yurgelun_2015), and Pancreatic Cancer (Shindo_2017, Ohmoto_2015). A publication, Yabuta_2002, reports the variant to segregate with disease in a HDGC family. Furthermore, a tumor obtained from a patient with this variant harbored a CDH1 promoter hypermethylation as a second hit leading to somatic loss of heterozygosity (Oliveira_2009). Co-occurrences with other pathogenic variant(s) have been reported (FANCI c.2737C>T, p.Q913X), providing supporting evidence for a benign role. Multiple functional studies showed no significant effect of this variant on cell mobility and cell invasion (Suriano_2003), interaction with alpha/beta catenin (Bajpai_2008), cell surface expression, EGFR signaling, and beta catenin binding (Mateaus_2009, Yabuta_2002, Curtis_2007). In addition, Clinical Genome Resource (ClinGen) variant curation expert panel (VCEP) recently classified this variant as benign (Lee_2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign x1, uncertain significance x4, and likely pathogenic x1). Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000013033 SCV000166556 likely benign Hereditary diffuse gastric cancer 2017-12-24 criteria provided, single submitter clinical testing
Mendelics RCV000013033 SCV000839100 uncertain significance Hereditary diffuse gastric cancer 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000013033 SCV000033278 pathogenic Hereditary diffuse gastric cancer 2002-10-10 no assertion criteria provided literature only
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000013033 SCV000267245 likely pathogenic Hereditary diffuse gastric cancer 2016-03-18 criteria provided, single submitter reference population

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