Submissions for variant NM_004360.5(CDH1):c.88C>A (p.Pro30Thr)

gnomAD frequency: 0.00129  dbSNP: rs139866691

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328180	SCV000864601	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.88C>A (p.Pro30Thr) variant has an allele frequency of 0.00249 (0.25%, 178/71372 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In addition to meeting stand along criteria for a benign classification, this variant has also been seen in >900 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, 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, BS2.
GeneDx	RCV000586357	SCV000149773	likely benign	not provided	2020-07-28	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: 25593300, 29958926, 26483394, 29348693, 29589180, 26022348, 27616075, 28944238, 27978560, 25637381, 28135145, 15831593, 10094558, 27443514, 27153395, 26759166, 27146957, 26976419, 26123647, 26072394, 25980754, 12800196, 20921021, 24493355, 23197654, 22470475, 24728327, none)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123256	SCV000166563	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115864	SCV000172834	benign	Hereditary cancer-predisposing syndrome	2014-08-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Illumina Laboratory Services, Illumina	RCV000123256	SCV000398547	likely benign	Hereditary diffuse gastric adenocarcinoma	2017-04-27	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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl	RCV000123256	SCV000488726	likely benign	Hereditary diffuse gastric adenocarcinoma	2016-05-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115864	SCV000537410	likely benign	Hereditary cancer-predisposing syndrome	2015-10-27	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120508	SCV000538647	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Detected in 2 patients with orofacial clefts (Vogelaar 2013). Gene is strongly asociated with gastric cancer, there is limited evidence for association with orofacial clefts.
Genetic Services Laboratory, University of Chicago	RCV000120508	SCV000593911	likely benign	not specified	2016-10-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000586357	SCV000806684	likely benign	not provided	2017-03-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586357	SCV000885153	likely benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586357	SCV000888043	benign	not provided	2022-11-15	criteria provided, single submitter	clinical testing
Mendelics	RCV000123256	SCV001140127	likely benign	Hereditary diffuse gastric adenocarcinoma	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120508	SCV001337977	benign	not specified	2020-01-23	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.88C>A (p.Pro30Thr) results in a non-conservative amino acid change located in the Cadherin prodomain (IPR014868) 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 0.0013 in 156216 control chromosomes. The observed variant frequency is approximately 47 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 benign. c.88C>A has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer. These reports 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 (MUTYH c.1227_1228dupGG, p.Glu410Glyfs*43; CTNNA1 c.76delGA, p.Arg27ThrfsX17; CHEK2 c.1100delC, p.T367fs*15), providing supporting evidence for a benign role. At least one publication reported experimental evidence evaluating an impact on protein function, demonstrating reduced localization of the variant protein to the plasma membrane, slightly decreased cell aggregation and minor increase in the invasion capacity of cells expressing the variant however, these results do not allow convincing conclusions about the variant effect (Vogelaar 2012). Thirteen clinical diagnostic laboratories and an expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (12x benign/likely benign, 1x VUS, expert panel benign). Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798349	SCV002043280	likely benign	Breast and/or ovarian cancer	2023-01-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115864	SCV002529220	benign	Hereditary cancer-predisposing syndrome	2020-10-22	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120508	SCV002551740	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586357	SCV002563347	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CDH1: BS1
Fulgent Genetics, Fulgent Genetics	RCV002490779	SCV002813088	likely benign	Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate	2022-04-19	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	RCV000123256	SCV003926970	benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BA1; BS2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000123256	SCV004020043	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-03-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
ITMI	RCV000120508	SCV000084661	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148455	SCV000190154	likely benign	Orofacial cleft	2014-06-01	no assertion criteria provided	research
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000123256	SCV000493725	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-01-27	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000120508	SCV000691811	uncertain significance	not specified		no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115864	SCV000787986	likely benign	Hereditary cancer-predisposing syndrome	2017-07-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000586357	SCV001549631	likely benign	not provided		no assertion criteria provided	clinical testing	The CDH1 p.Pro30Thr variant was identified in 5 of 3312 proband chromosomes (frequency: 0.0015) from individuals or families with lobular breast cancer and Lynch syndrome and was present in 11 of 17412 control chromosomes (frequency: 0.0006) from healthy individuals (Molinaro 2014, Sarrio 2003, Schrader 2011, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs139866691) as “With other allele”, ClinVar (as benign by Invitae and Ambry Gentics, likely benign by GeneDx, Illumina, Counsyl, Color Genomics, Laboratory for Molecular Medicine, University of Chicago, and University of Washington Medical Center, and as uncertain significance by Knight Diagnostic Laboratories), Clinvitae (4x with conflicting interpretations of pathogenicity), Cosmic (seen in breast cancer), Insight Colon Cancer Gene Variant Database (2x), and Zhejiang Colon Cancer Database (2x). The variant was not identified in the MutDB database. The variant was identified in control databases in 232 of 178576 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 3 of 15728 chromosomes (freq: 0.0002), Other in 11 of 4718 chromosomes (freq: 0.002), Latino in 31 of 24390 chromosomes (freq: 0.001), European in 178 of 71372 chromosomes (freq: 0.002), Finnish in 3 of 19552 chromosomes (freq: 0.0002), and South Asian in 6 of 22566 chromosomes (freq: 0.0003), while the variant was not observed in the Ashkenazi Jewish or East Asian populations. In a functional study in which RT-PCR was performed, the protein transcript was found to be normal (Molinaro 2014). A study of CDH1 variants in Hereditary Diffuse Gastric Cancer (HDGC) patients using in silico tools concluded the variant was structurally tolerated (Simoes Correia 2012). The variant was also found in 2 patients with orofacial clefts; during embryonic development, the cell adhesion molecule E-cadherin, encoded by CDH1, is highly expressed in the median edge epithelium of the palate (Vogelaar 2013). The p.Pro30 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, 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.