Submissions for variant NM_004360.5(CDH1):c.879G>A (p.Val293=)

gnomAD frequency: 0.00001  dbSNP: rs778959722

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165235	SCV000215949	likely benign	Hereditary cancer-predisposing syndrome	2014-07-18	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.
Invitae	RCV000457686	SCV000557395	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165235	SCV000684492	likely benign	Hereditary cancer-predisposing syndrome	2016-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174749	SCV001338066	likely benign	not specified	2020-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001356033	SCV001835764	benign	not provided	2015-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001356033	SCV001961601	likely benign	not provided	2021-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165235	SCV002529219	likely benign	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003907521	SCV004721787	likely benign	CDH1-related disorder	2023-04-25	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	RCV001356033	SCV001551087	likely benign	not provided		no assertion criteria provided	clinical testing	The CDH1 p.Val293= variant was not identified in the literature nor was it identified in the databases. The variant was identified in dbSNP (ID: rs778959722) “With Likely benign allele”, and ClinVar (classified likely benign by Ambry Genetics, Inivitae and Color). The variant was identified in control databases in 2 of 246252 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017), observed in the following population: European Non-Finnish in 2 of 111700 chromosomes (freq: 0.00002), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Val293= 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 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.