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

gnomAD frequency: 0.00004  dbSNP: rs35572355

Total submissions: 19

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	RCV004579526	SCV000033278	pathogenic	DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME	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