Submissions for variant NM_004360.5(CDH1):c.1296C>T (p.Asn432=)

gnomAD frequency: 0.00019  dbSNP: rs187862045

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164680	SCV000215347	likely benign	Hereditary cancer-predisposing syndrome	2014-12-11	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	RCV000199519	SCV000253406	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164680	SCV000689442	likely benign	Hereditary cancer-predisposing syndrome	2017-06-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251379	SCV001426954	benign	not specified	2020-07-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001651035	SCV001869655	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798586	SCV002043250	likely benign	Breast and/or ovarian cancer	2020-11-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001251379	SCV002047231	benign	not specified	2021-06-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164680	SCV002531155	likely benign	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV003895132	SCV004715600	likely benign	CDH1-related disorder	2022-12-20	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	RCV001358146	SCV001553808	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Asn432= variant was not identified in the literature nor was it identified in the databases. The variant was also identified in dbSNP (ID: rs187862045) as "With Likely benign, Uncertain significance allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics and Color). The variant was identified in control databases in 17 of 277234 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 2 of 34420 chromosomes (freq: 0.00006), Finnish in 14 of 25794 chromosomes (freq: 0.0005), while the variant was not observed in the African, European, Ashkenazi Jewish, East Asian, and South Asian populations. The p.Asn432= 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. 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.