Submissions for variant NM_004360.5(CDH1):c.2512A>G (p.Ser838Gly)

gnomAD frequency: 0.00011  dbSNP: rs121964872

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328149	SCV000864627	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.2512A>G (p.Ser838Gly) 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	RCV001719696	SCV000149766	likely benign	not provided	2019-06-12	criteria provided, single submitter	clinical testing	In-silico analyses, including protein predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging; This variant is associated with the following publications: (PMID: 25801821, 29929997, 30374176, 8075649, 22470475, 25980754, 19139070, 10671552, 26674224, 27616075, 28993866, 9823469, 28767289, 31159747)
Ambry Genetics	RCV000115857	SCV000183966	likely benign	Hereditary cancer-predisposing syndrome	2018-11-09	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198450	SCV000254825	likely benign	Hereditary diffuse gastric adenocarcinoma	2025-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000198450	SCV000487808	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2015-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212390	SCV000698387	likely benign	not specified	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2512A>G (p.Ser838Gly) results in a non-conservative amino acid change located in the Cadherin, cytoplasmic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 273974 control chromosomes (gnomAD and publication), predominantly at a frequency of 9.7e-05 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 5 fold of our internal estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Breast and Ovarian Cancer phenotype (2.1e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. However, this frequency does not exceed the allele frequency threshold of 0.001 set by the ClinGen CDH1 variant curation expert panel (Lee_2018). c.2512A>G has been reported in the literature in individuals affected with cancer, including breast cancer, Lynch syndrome-associated cancer and pancreatic neuroendocrine tumor (examples: Hauke_2018, Shindo_2017, Tung_2015, Yurgelun_2015, Schubert_2019). In one study, the variant was detected in an unaffected female proband (45 years old) from a BRCA1-positive ( c.1016dupA, p.Val340fsX6) family with a history of breast and ovarian cancer (Stuebs_2018). In another study, 5 individuals older than 55 were reported in one family who had the variant but did not have gastric cancer, and only one had breast cancer (Tsai_2019). Another co-occurrence with a pathogenic variant has been reported in our internal database (BRCA2 c.6025C>T, p.Gln2009X), providing supporting evidence for a benign role. Furthermore, the variant of interest was detected in 2 women in the FLOSSIES database older than age 70 years who have never had cancer, providing further supporting evidence for a benign role. Multiple 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 (VUS, n=6, likely benign n=7). The expert panel has re-classified this variant as likely benign since its previous evaluation by our laboratory. Based on the evidence outlined above, as all ascertained evidence supports a likely benign outcome in accordance with the proposed CDH1-expert panel conclusion, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000198450	SCV000788250	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-05-26	criteria provided, single submitter	research	The CDH1 variant designated as NM_004360.3:c.2512A>G (p.Ser838Gly) is classified as likely benign in the context of hereditary diffuse gastric cancer syndrome (Hansford 2015, PMID:26182300). This variant was identified or imputed in several family members age 65 or older who have not had gastric cancer or lobular breast cancer. This variant is listed in population databases (rs121964872) and is found in approximately 1 out of 9000 individuals of European ancestry (http://gnomad.broadinstitute.org/). This variant is predicted to be tolerated by in silico prediction tools (SIFT, PolyPhen-2, Align-GVGD). Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to cause hereditary diffuse gastric cancer syndrome. A smaller increase in cancer risk that the risk reported in the literature due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
GeneKor MSA	RCV000115857	SCV000821975	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115857	SCV000910736	likely benign	Hereditary cancer-predisposing syndrome	2015-12-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000198450	SCV001140155	benign	Hereditary diffuse gastric adenocarcinoma	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000198450	SCV001274534	uncertain significance	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253384	SCV001429064	uncertain significance	Familial cancer of breast	2018-09-11	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001719696	SCV002009853	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115857	SCV002529144	likely benign	Hereditary cancer-predisposing syndrome	2020-10-12	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490358	SCV002799939	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2021-09-29	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	RCV000198450	SCV003926957	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000198450	SCV004020042	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
CeGaT Center for Human Genetics Tuebingen	RCV001719696	SCV004140036	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BS2
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719696	SCV004220825	likely benign	not provided	2022-08-08	criteria provided, single submitter	clinical testing
OMIM	RCV000013020	SCV000033265	pathogenic	Ovarian neoplasm	1994-05-01	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003944817	SCV004765348	likely benign	CDH1-related disorder	2020-11-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).