Submissions for variant NM_004360.5(CDH1):c.2637C>T (p.Gly879=)

gnomAD frequency: 0.00006  dbSNP: rs141001592

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163107	SCV000213616	likely benign	Hereditary cancer-predisposing syndrome	2014-12-22	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	RCV001085146	SCV000254828	benign	Hereditary diffuse gastric adenocarcinoma	2024-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000437397	SCV000515549	likely benign	not specified	2018-01-25	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.
Color Diagnostics, LLC DBA Color Health	RCV000163107	SCV000684448	likely benign	Hereditary cancer-predisposing syndrome	2016-05-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588174	SCV000698392	benign	not provided	2017-02-02	criteria provided, single submitter	clinical testing	Variant summary: The CDH1 c.2637C>T (p.Gly879Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change in the last exon (10bp upstream of the stop codon). One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. 5/5 splice prediction tools predict a gain of a cryptic splicing donor site. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 6/121264 control chromosomes at a frequency of 0.0000495, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283), suggesting this variant is likely a benign polymorphism. This variant was reported in Wilms' tumor sample without germline status confirmed. One internal sample also carried a pathogenic variant in BRIP1 c.3651G>A/p.W1217*, futher supporting the benign nature of this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798568	SCV002043277	likely benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163107	SCV002529162	benign	Hereditary cancer-predisposing syndrome	2021-03-04	criteria provided, single submitter	curation
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV001085146	SCV003926973	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2_Supporting; BP7 (PMID: 30311375)
CeGaT Center for Human Genetics Tuebingen	RCV000588174	SCV004140038	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	CDH1: BP4, BP7
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000588174	SCV001552217	likely benign	not provided		no assertion criteria provided	clinical testing	The CDH1 p.Gly879= variant was identified in 1 of 270 proband chromosomes (frequency: 0.004) from individuals or families with carcinomas of the endometrium and ovary (Risinger 1994). The variant was also identified in the following databases: dbSNP (ID: rs141001592) as "With Likely benign allele", ClinVar (3x likely benign, 2x benign), Clinvitae, and the Zhejiang Colon Cancer Database (1x). The variant was not identified in Cosmic, MutDB, or the Insight Colon Cancer Gene Variant Database. The variant was identified in control databases in 15 of 246200 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 4 of 15304 chromosomes (freq: 0.0003), European in 7 of 111662 chromosomes (freq: 0.00006), East Asian in 2 of 17248 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.00007). The variant was not observed in the Other, Latino, Ashkenazi Jewish, or Finnish populations. Multiple studies have listed this variant as a polymorphism (Berx 1998, Risinger 1994). The p.Gly879= 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. However, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% 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.