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

gnomAD frequency: 0.00013  dbSNP: rs200911775

Total submissions: 18

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123251	SCV000166558	likely benign	Hereditary diffuse gastric adenocarcinoma	2025-01-30	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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212393	SCV000698391	likely benign	not specified	2024-11-11	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2635G>A (p.Gly879Ser) results in a non-conservative amino acid change located in the cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 277608 control chromosomes, predominantly at a frequency of 0.00025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 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 Non-Finnish European origin. c.2635G>A has been reported in the literature in individuals with suspected Lynch syndrome or affected with lobular breast cancer (Valente_2014, Yurgelun_ 2015) without strong evidence of causality. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754, 25067988, 26123647, 28166811, 30311375, 30287823). ClinVar contains an entry for this variant (Variation ID: 127928). Based on the evidence outlined above, the variant was classified as likely benign.
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	2025-02-01	criteria provided, single submitter	clinical testing	CDH1: BS2
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212393	SCV002760870	likely benign	not specified	2025-03-04	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