Submissions for variant NM_004360.5(CDH1):c.32TGC[7] (p.Leu14_Leu15dup)

dbSNP: rs587782476

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328224	SCV001365451	likely benign	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-18	reviewed by expert panel	curation	The c.32_34TGC[7] (p.Leu14_Leu15dup) variant results in an in-frame insertion in exon 1. This variant has a frequency of 0.0008% in gnomAD (1 of 124,448) (PM2_Supporting; https://gnomad.broadinstitute.org/). However, this region has poor coverage and allele frequency estimates may not be reliable. This variant has also been identified in at least ten individuals without DGC, SRC tumours and LBC and whose families do not suggest HDGC (BS2, SCV000569203.4, SCV000186596.5, SCV000545430.4). 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, PM2_Supporting.
Ambry Genetics	RCV000131585	SCV000186596	likely benign	Hereditary cancer-predisposing syndrome	2023-06-28	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	RCV000473416	SCV000545430	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2024-01-18	criteria provided, single submitter	clinical testing	This variant, c.41_46dup, results in the insertion of 2 amino acid(s) of the CDH1 protein (p.Leu14_Leu15dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587782476, gnomAD 0.005%). This variant has been observed in individual(s) with breast cancer (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 142455). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000480757	SCV000569203	likely benign	not provided	2020-11-13	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In-frame insertion of 2 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge
Color Diagnostics, LLC DBA Color Health	RCV000131585	SCV000689536	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This variant is a two amino acid duplication located in exon 1 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. 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.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000473416	SCV003926715	likely benign	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	BS2, PM2 (PMID: 30311375)