Submissions for variant NM_004360.5(CDH1):c.188G>A (p.Arg63Gln)

gnomAD frequency: 0.00002  dbSNP: rs587780117

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328173	SCV000864612	benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-10	reviewed by expert panel	curation	The c.188G>A (p.Arg63Gln) variant has an allele frequency of 0.00109 (0.11%, 6/5486 alleles) in the Other subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 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): BS1, BS2.
GeneDx	RCV000679566	SCV000149757	likely benign	not provided	2020-12-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115848	SCV000185341	benign	Hereditary cancer-predisposing syndrome	2018-05-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226241	SCV000288450	benign	Hereditary diffuse gastric adenocarcinoma	2025-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115848	SCV000910840	likely benign	Hereditary cancer-predisposing syndrome	2015-09-09	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000679566	SCV002009860	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001796964	SCV002071976	likely benign	not specified	2021-11-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115848	SCV002529099	benign	Hereditary cancer-predisposing syndrome	2021-09-18	criteria provided, single submitter	curation
Institute of Human Genetics, University of Leipzig Medical Center	RCV000226241	SCV003921059	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-02-22	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: BS1, BP4
Myriad Genetics, Inc.	RCV000226241	SCV005404177	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-09-12	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.
PreventionGenetics, part of Exact Sciences	RCV003891615	SCV000806647	likely benign	CDH1-related disorder	2021-02-23	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).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000226241	SCV001553806	uncertain significance	Hereditary diffuse gastric adenocarcinoma		no assertion criteria provided	clinical testing	The CDH1 p.Arg63Gln variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or in the Zhejiang University database. The variant was identified in dbSNP (ID: rs587780117) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by GeneDx, Ambry Geneitcs, Invitae). The variant was identified in control databases in 17 of 246200 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15304 chromosomes (freq: 0.00007), Other in 6 of 5486 chromosomes (freq: 0.001), European in 3 of 111650 chromosomes (freq: 0.00003), and South Asian in 7 of 30782 chromosomes (freq: 0.0002); it was not observed in the Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Arg63 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.