Submissions for variant NM_004360.5(CDH1):c.2165-15C>A

gnomAD frequency: 0.00004  dbSNP: rs552874184

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160377	SCV000210886	benign	not specified	2014-06-13	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.
Illumina Laboratory Services, Illumina	RCV000280140	SCV000398578	likely benign	Hereditary diffuse gastric adenocarcinoma	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579634	SCV000684403	likely benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000280140	SCV000785997	likely benign	Hereditary diffuse gastric adenocarcinoma	2018-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000280140	SCV001732619	benign	Hereditary diffuse gastric adenocarcinoma	2024-02-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579634	SCV002529110	likely benign	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000280140	SCV004020002	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-03-06	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355512	SCV001550424	likely benign	not provided		no assertion criteria provided	clinical testing	The CDH1 c.2165-15C>A variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Insight Colon Cancer Gene Variant, and Zhejiang Colon Cancer databases. The variant was identified in the following databases: dbSNP (ID: rs552874184) as “with likely benign allele”, in ClinVar and Clinvitae databases as benign by GeneDx and likely benign by Illumina Clinical Services. The variant was also identified in the 1000 Genomes Project in 3 of 5000 chromosomes (frequency: 0.0006). Furthermore, the variant was identified in control databases in 33 of 277016 chromosomes at a frequency of 0.0001 in the following populations: East Asian in 32 of 18868 chromosomes (freq. 0.002), and South Asian in 1 of 30780 chromosomes (freq. 0.00003), but was not seen in the African, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and other populations, increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.