ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.2635G>A (p.Gly879Ser)

gnomAD frequency: 0.00013  dbSNP: rs200911775
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328178 SCV000864613 likely benign CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-17 reviewed by expert panel curation The c.2635G>A (p.Gly879Ser) 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, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
GeneDx RCV000985661 SCV000149768 likely benign not provided 2020-10-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26123647, 25067988, 25980754, 25925381, 30287823)
Invitae RCV000123251 SCV000166558 likely benign Hereditary diffuse gastric adenocarcinoma 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115859 SCV000186401 likely benign Hereditary cancer-predisposing syndrome 2018-09-26 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.
Color Diagnostics, LLC DBA Color Health RCV000115859 SCV000684447 likely benign Hereditary cancer-predisposing syndrome 2020-03-04 criteria provided, single submitter clinical testing
Mendelics RCV003492499 SCV000839101 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985661 SCV001134088 likely benign not provided 2022-12-03 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001253473 SCV001429189 uncertain significance Familial cancer of breast 2018-09-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212393 SCV002066690 likely benign not specified 2020-04-20 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115859 SCV002529161 likely benign Hereditary cancer-predisposing syndrome 2022-01-06 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000985661 SCV002545806 likely benign not provided 2022-06-01 criteria provided, single submitter clinical testing CDH1: BP1, BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212393 SCV002760870 likely benign not specified 2023-08-15 criteria provided, single submitter clinical testing
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000123251 SCV003926972 likely benign Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing BS2 (PMID: 30311375)
PreventionGenetics, part of Exact Sciences RCV003407500 SCV004115996 uncertain significance CDH1-related disorder 2022-08-25 criteria provided, single submitter clinical testing The CDH1 c.2635G>A variant is predicted to result in the amino acid substitution p.Gly879Ser. This variant has been reported in individuals with a history of breast cancer and suspected Lynch syndrome (Table 2, Valente et al. 2014. PubMed ID: 25067988; Supplemental Table 2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68867388-G-A). This variant has been classified as likely benign by an expert panel in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/127928). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355027 SCV001549785 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CDH1 p.Gly879Ser variant was identified in 4 of 16,822 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer or lynch syndrome and was present in 1 of 47,462 control chromosomes (frequency: 0.00002) from healthy individuals (Momozawa 2018, Yurgelun 2015, Valente 2014). The variant was identified in dbSNP (rs200911775) as ‚ with other allele‚Äù and ClinVar (classified as uncertain significance by ClinGen CDH1 Curation Panel, Invitae, Color and 1 other submitter; and as likely benign by Ambry Genetics, GeneDx and Integrated Genetics). The variant was identified in control databases in 37 of 282,800 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 7218 chromosomes (freq: 0.0003), European in 32 of 129,134 chromosomes (freq: 0.0002), African in 1 of 24,964 chromosomes (freq: 0.00004), Finnish in 1 of 25,106 chromosomes (freq: 0.00004), and Latino in 1 of 35,440 chromosomes (freq: 0.00003); it was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The p.Gly879 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. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000985661 SCV002035131 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000985661 SCV002035896 likely benign not provided no assertion criteria provided clinical testing

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