ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1888C>G (p.Leu630Val)

gnomAD frequency: 0.00009  dbSNP: rs2276331
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328185 SCV000864603 benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-08 reviewed by expert panel curation The c.1888C>G (p.Leu630Val) variant has an allele frequency of 0.00519 (0.52%, 98/18,866 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 (Variant Interpretation Guidelines Version 3.1): BA1.
Ambry Genetics RCV000131132 SCV000186064 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
GeneDx RCV001704034 SCV000210921 likely benign not provided 2020-07-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 30022640, 29770616, 25980754, 23431106, 26757417, 27227907, 26707089, 25648022, 24728327, 28580595, 29212164, 32426482)
Invitae RCV000195597 SCV000252791 benign Hereditary diffuse gastric adenocarcinoma 2024-02-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001704034 SCV000600967 benign not provided 2022-10-27 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131132 SCV000684386 likely benign Hereditary cancer-predisposing syndrome 2015-09-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120498 SCV000917133 likely benign not specified 2018-08-03 criteria provided, single submitter clinical testing Variant summary: CDH1 c.1888C>G (p.Leu630Val) results in a conservative amino acid change located in the Cadherin 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 183.84 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. The variant allele was found at a frequency of 0.00037 in 277212 control chromosomes, predominantly at a frequency of 0.0052 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 250 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast and Ovarian Cancer phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1888C>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRIP1 del exons 4-5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Cancer Genomics Group, Japanese Foundation For Cancer Research RCV001030612 SCV001193546 likely benign Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Illumina Laboratory Services, Illumina RCV000195597 SCV001277758 benign Hereditary diffuse gastric adenocarcinoma 2017-04-28 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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798384 SCV002043259 likely benign Breast and/or ovarian cancer 2021-05-12 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131132 SCV002529098 benign Hereditary cancer-predisposing syndrome 2020-08-29 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 RCV000195597 SCV003926865 benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BA1 (PMID: 30311375)
ITMI RCV000120498 SCV000084651 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356003 SCV001551050 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Leu630Val variant was identified in 3 of 512 proband chromosomes (frequency: 0.006) from individuals or families with gastric cancer or oral cleft and was present in 2 of 480 control chromosomes (frequency: 0.004) from healthy individuals (Chen 2013, Huang 2017). The variant was also identified in dbSNP (ID: rs2276331) as "With other allele", ClinVar (classified as benign by ClinGen CDH1 Variant Curation Expert Panel, Ambry Genetics, Invitae; and as likely benign by GeneDx, Quest Diagnostics, Color Genomics). The variant was identified in control databases in 102 of 277212 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 3 of 6464 chromosomes (freq: 0.0005), East Asian in 98 of 18866 chromosomes (freq: 0.005), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, or Finnish, populations. Two studies assessed the p.Leu630Val variant using in silico analysis and consider it to be “probably damaging”, however it was recommended that in vitro studies would be necessary to confirm the findings (Chen 2013, Santhiya 2013). The p.Leu630 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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