Submissions for variant NM_004360.5(CDH1):c.378G>A (p.Pro126=)

gnomAD frequency: 0.00002  dbSNP: rs786201504

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163770	SCV000214351	likely benign	Hereditary cancer-predisposing syndrome	2015-04-22	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	RCV000550435	SCV000637823	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001697090	SCV000725112	likely benign	not provided	2021-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163770	SCV000906522	likely benign	Hereditary cancer-predisposing syndrome	2016-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000609083	SCV000919094	likely benign	not specified	2019-08-28	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357491	SCV001552976	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CDH1 p.Pro126= variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs786201504) as With Likely benign allele, ClinVar (classified as likely benign by Ambry Genetics, Invitae, GeneDx) and Clinvitae. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Pro126= 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, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified with a co-occurring pathogenic variant (BRCA2, c.6313delA) in one individual with a diagnosis of breast cancer from our laboratory, increasing the likelihood this variant does not have clinical significance. 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.