Submissions for variant NM_004360.5(CDH1):c.1266A>G (p.Gln422=)

gnomAD frequency: 0.00001  dbSNP: rs776805501

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165374	SCV000216101	likely benign	Hereditary cancer-predisposing syndrome	2014-07-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000546507	SCV000637708	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165374	SCV000684347	likely benign	Hereditary cancer-predisposing syndrome	2017-02-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000603146	SCV000732593	likely benign	not specified	2018-01-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl	RCV000546507	SCV000786315	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-04-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800490	SCV002046330	likely benign	not provided	2020-10-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000546507	SCV004019528	benign	Hereditary diffuse gastric adenocarcinoma	2023-03-03	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358058	SCV001553702	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Gln422= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs776805501) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics, Color, GeneDx and Counsyl; as uncertain significance by Invitae). The variant was identified in control databases in 3 of 246264 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 2 of 111714 chromosomes (freq: 0.00002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish populations. The p.Gln422= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The nucleotide is not highly conserved and an A>G substitution is observed in several mammalian species. 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.