ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs35572355
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328157 SCV000864595 benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-10 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 (Variant Interpretation Guidelines Version 3.1): BS1, BS2.
GeneDx RCV000587650 SCV000149765 likely benign not provided 2019-09-13 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 12216071, 26759166, 28004449, 26692440, 20373070, 29050249, 16924464, 19268661, 22850631, 24055113, 24728327, 17668349, 12944922, 17261850, 16600987, 25388006, 25856671, 25637381, 17545690, 20233471, 26150395, 20921021, 16787116, 28503720, 14500541, 19269290, 26049741, 25980754, 22470475, 19017792, 29231860, 28975465, 28767289, 29522266, 29929997, 29752822, 16112667, 21989054, 19247957, 31159747, 31892987, 32426482)
Invitae RCV000013033 SCV000166556 likely benign Hereditary diffuse gastric adenocarcinoma 2024-01-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115856 SCV000183955 likely benign Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center RCV000013033 SCV000267245 likely pathogenic Hereditary diffuse gastric adenocarcinoma 2016-03-18 criteria provided, single submitter reference population
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120506 SCV000698386 benign not specified 2020-12-18 criteria provided, single submitter clinical testing Variant summary: 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 variant allele was found at a frequency of 0.00022 in 253888 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database. 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 phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. 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). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At-least two co-occurrences with other pathogenic variant(s) have been observed (Siraj_2017-FANCI c.2737C>T, p.Q913X; our laboratory-BRCA2 c.5576_5579delTTAA, p.Ile1859fs), 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). Ten clinical diagnostic laboratories and one expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters reported the variant with conflicting assessments (likely benign, n=3, benign, n=1). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA RCV000115856 SCV000821974 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000013033 SCV000839100 benign Hereditary diffuse gastric adenocarcinoma 2023-08-22 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115856 SCV000902855 likely benign Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587650 SCV001134086 uncertain significance not provided 2019-12-27 criteria provided, single submitter clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research RCV001030616 SCV001193550 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Institute of Human Genetics, University of Leipzig Medical Center RCV000013033 SCV001428521 uncertain significance Hereditary diffuse gastric adenocarcinoma 2018-08-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115856 SCV002529143 likely benign Hereditary cancer-predisposing syndrome 2021-03-11 criteria provided, single submitter curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000013033 SCV003926956 benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BS1; BS2 (PMID: 30311375)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120506 SCV004026659 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003952353 SCV004773505 benign CDH1-related disorder 2020-01-21 criteria provided, single submitter clinical testing This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM RCV000013033 SCV000033278 pathogenic Hereditary diffuse gastric adenocarcinoma 2002-10-10 no assertion criteria provided literature only
ITMI RCV000120506 SCV000084659 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148456 SCV000190155 likely pathogenic Neoplasm of stomach 2014-06-01 no assertion criteria provided research

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