Submissions for variant NM_004360.5(CDH1):c.32TGC[6] (p.Leu15dup)

dbSNP: rs587782476

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328271	SCV001437632	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-17	reviewed by expert panel	curation	The c.32_34TGC[6] (p.Leu15dup), also referred to as 46insTGC, results in the in-frame insertion of a leucine residue in exon 1. This variant has been observed in more than 10 individuals with DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000566421.3, SCV000261647.7). This variant has also been reported in the literature in an HDGC family, but it is not known whether this family meets current IGCLC criteria (PMID: 20373070). In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
Invitae	RCV000206215	SCV000261647	likely benign	Hereditary diffuse gastric adenocarcinoma	2023-11-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000206215	SCV000489482	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2016-10-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000481833	SCV000566421	uncertain significance	not provided	2023-08-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 1 amino acid in a repetitive region with no known function; Observed in a hereditary diffuse gastric cancer (HDGC) family as well as individuals with personal or family history of breast cancer (Guilford et al., 2010; Rodriguez-Balada et al., 2020; Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 15235021, 22225527, 20373070, 30068367, 31786208, 34855780, 36436516, 36243179, 32980694)
Color Diagnostics, LLC DBA Color Health	RCV000579612	SCV000684460	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This variant causes a duplication of a leucine residue at codon 15 of the CDH1 protein, following 5 consecutive leucine residues. This variant is also known as 46insTGC in the literature. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary diffuse gastric cancer (PMID: 20373070), as well as in individuals and families whose phenotype is not consistent with hereditary diffuse gastric cancer (ClinVar SCV001437632.1; Color internal data). This variant has been identified in 1/124448 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481833	SCV001470281	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in affected families with hereditary diffuse gastric cancer (PMID: 20373070 (2010)), as well as in an affected individual with breast cancer (PMID: 31786208 (2020)). The frequency of this variant in the general population, 0.000008 (1/124448 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000579612	SCV002529184	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	curation
Ambry Genetics	RCV000579612	SCV002631265	likely benign	Hereditary cancer-predisposing syndrome	2022-03-05	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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000206215	SCV003926737	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2 (PMID: 30311375)
Myriad Genetics, Inc.	RCV000206215	SCV004044097	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-05-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493507	SCV004242719	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing