Submissions for variant NM_004360.5(CDH1):c.2369C>T (p.Thr790Ile)

gnomAD frequency: 0.00001  dbSNP: rs587780120

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212386	SCV000149762	uncertain significance	not provided	2024-02-28	criteria provided, single submitter	clinical testing	Observed in individuals with colon and/or breast cancer, but also present in controls groups (PMID: 28135145, 30287823, 35402282); Absent in individuals with isolated orofacial clefting, but observed in one control for whom personal and family cancer history is unknown (PMID: 26123647); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28135145, 30287823, 35402282, 15235021, 22850631, 26123647, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123246	SCV000166552	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115853	SCV000172823	likely benign	Hereditary cancer-predisposing syndrome	2020-10-06	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.
Color Diagnostics, LLC DBA Color Health	RCV000115853	SCV000684428	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 790 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer in the literature (PMID: 28135145) but also in unaffected controls (PMID: 30287823). This variant has been identified in 3/282826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280598	SCV001467808	uncertain significance	not specified	2020-12-03	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.2369C>T (p.Thr790Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251468 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2369C>T has been reported in the literature in an individual affected with Colorectal Cancer (Yurgelun_2017). This report however does not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001293918	SCV001482611	uncertain significance	Blepharocheilodontic syndrome 1	2019-01-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149806	SCV003837770	uncertain significance	Breast and/or ovarian cancer	2023-06-12	criteria provided, single submitter	clinical testing