Submissions for variant NM_004360.5(CDH1):c.670C>T (p.Arg224Cys)

gnomAD frequency: 0.00021  dbSNP: rs200310662

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328179	SCV000864585	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.670C>T (p.Arg224Cys) 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	RCV000858545	SCV000149772	likely benign	not provided	2020-12-03	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26182300, 21106365, 25980754, no PMID, 25593300, 26893459, 27582386, 28301460, 27621404, 30311375, 29577179)
Invitae	RCV000123253	SCV000166560	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115863	SCV000186163	likely benign	Hereditary cancer-predisposing syndrome	2018-08-28	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.
Paul Sabatier University EA-4555, Paul Sabatier University	RCV000207407	SCV000259124	likely benign	Anophthalmia-microphthalmia syndrome	2013-01-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115863	SCV000684476	likely benign	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212353	SCV000698407	benign	not specified	2019-05-30	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.670C>T (p.Arg224Cys) results in a non-conservative amino acid change located in the Cadherin 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 0.00018 in 251344 control chromosomes, predominantly at a frequency of 0.00027 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 9.5 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 (ACMG BS1). c.670C>T has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer, breast cancer, and colon cancer (Corso_2011, Harismendy_2013, Mouradov_2014, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. Co-occurrences with other pathogenic variant(s) have been reported at our laboratory (APC c.5582_5585delCTTT, p.Ser1861fsX1) as well as a co-occurence with a mutation in another gene (not explicitly specified) that clearly explains a proband's phenotype as mentioned in the supporting evidence shared by another submitting laboratory to the ClinVar database. These findings providing supporting evidence for a benign role (ACMG BP5). Cells expressing the p.Arg224Cys sequence variant maintained the ability to form compact aggregates at a similar level to that of the wild-type CDH1 expressing cells and retained capacity to prevent invasion in clear contrast to what was observed for mock cells; therefore, the c.670C>T (p.Arg224Cys) missense mutation does not impair E-cadherin induced cell adhesion and invasion in vitro (Corso_2011). However, an expert panel (ClinGen Hereditary Cancer) has reviewed the available literature and stated "none of the currently published in vitro and in vivo functional studies could be confidently used to predict pathogenicity of E-cadherin missense variants and therefore functional assays for missense alteration should not be used for CDH1 variant classificat" (Thompson_2018). Four clinical diagnostic laboratories and one expert panel (ClinGen Hereditary Cancer Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All labs classified the variant as likely benign while the expert panel classified the variant as VUS based on BS2 as the only criteria met by this variant. A follow-up with Dr. Xuo Li as the ClinGen CDH1 contact indicated that the committee was in agreement that a single BS code is sufficient to reach a likely benign classification, although it was not officially released at the time of this re-evaluation and a new version of the guideline was to be expected (personal correspondence, 05-14-19). Based on the evidence outlined above, we have utilized ACMG criteria BS2 (Expert Panel evidence) along with BS1 and BP5 (summarized above) and classified the variant as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000858545	SCV001134093	likely benign	not provided	2022-09-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000123253	SCV001140134	likely benign	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798348	SCV002043279	likely benign	Breast and/or ovarian cancer	2021-03-10	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115863	SCV002529202	likely benign	Hereditary cancer-predisposing syndrome	2021-02-19	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490778	SCV002808476	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Neoplasm of ovary; Malignant tumor of prostate	2021-08-12	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	RCV000123253	SCV003926673	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2 (PMID: 30311375)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315643	SCV004017004	likely benign	Malignant tumor of prostate	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212353	SCV004026634	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003935105	SCV004749679	likely benign	CDH1-related disorder	2024-02-16	criteria provided, single submitter	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357912	SCV001553512	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Arg224Cys variant was identified in the literature however the frequency of this variant in an affected population was not provided (Corso 2011). The variant was also identified in dbSNP (ID: rs200310662) as “With Likely benign” and “Uncertain significance allele”, ClinVar (as likely benign by GeneDx, Invitae, Ambry Genetics, and Paul Sabatier University), Clinvitae (as likely benign), Cosmic (in large intestine and breast tissue), and LOVD 3.0 (1x as "effect unknown"). The variant was not identified in MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database. The variant was identified in control databases in 47 of 276620 chromosomes at a frequency of 0.00017 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2 of 24024 chromosomes (freq: 0.000083), Latino in 1 of 34400 chromosomes (freq: 0.000029), European (Non-Finnish) in 35 of 126242 chromosomes (freq: 0.000277), European (Finnish) in 1 of 25758 chromosomes (freq: 0.000039), and South Asian in 8 of 30760 chromosomes (freq: 0.00026) while the variant was not observed in the Other, Ashkenazi Jewish, and East Asian populations. A functional analysis by Corso et al (2011) in which they compared the cell adhesion activity of the variant, they found the p.Arg224Cys expressing cells behaved in a similar manner to cells transduced with the wild-type CDH1. The study therefore concluded that the variant is non-pathogenic. In addition, the variant has been found in our lab to co-occur with a pathogenic BRCA1 variant c.135-1G>T, increasing the likelihood that the p.Arg224Cys variant does not have clinical significance. The p.Arg224Cys residue is not 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, HumanSpliceFinder) 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000858545	SCV001808371	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000858545	SCV001959692	likely benign	not provided		no assertion criteria provided	clinical testing