Submissions for variant NM_004360.5(CDH1):c.49-3C>A

dbSNP: rs587782366

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen CDH1 Variant Curation Expert Panel	RCV003328360	SCV001437600	uncertain significance	CDH1-related diffuse gastric and lobular breast cancer syndrome	2023-08-21	reviewed by expert panel	curation	The c.49-3C>A variant has been observed in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_supporting; SCV000822625.1, SCV000570129.4, SCV000665064.2). In summary, the clinical significance of this variant is uncertain based on ACMP/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting.
GeneDx	RCV000485775	SCV000570129	uncertain significance	not provided	2016-04-27	criteria provided, single submitter	clinical testing	This variant is denoted CDH1 c.49-3C>A or IVS1-3C>A and consists of a C>A nucleotide substitution at the -3 position of intron 1 of the CDH1 gene. Multiple in silico models predict this variant may disrupt the nearby natural splice acceptor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 c.49-3C>A was not observed in approximately 4,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The cytosine (C) nucleotide that is altered is conserved among mammals. Based on currently available information, it is unclear whether CDH1 c.49-3C>A is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000567837	SCV000665064	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-10	criteria provided, single submitter	clinical testing	The c.49-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 2 in the CDH1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000694193	SCV000822625	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2023-11-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 of the CDH1 gene. It does not directly change the encoded amino acid sequence of the CDH1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 421050). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Color Diagnostics, LLC DBA Color Health	RCV000567837	SCV001735080	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-10	criteria provided, single submitter	clinical testing	This variant causes a C to A nucleotide substitution at the -3 position of intron 1 of the CDH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Baylor Genetics	RCV003476168	SCV004210562	uncertain significance	Familial cancer of breast	2022-07-19	criteria provided, single submitter	clinical testing