Submissions for variant NM_004360.5(CDH1):c.531+3A>G

gnomAD frequency: 0.00002  dbSNP: rs766563354

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221748	SCV000274161	likely benign	Hereditary cancer-predisposing syndrome	2022-01-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461908	SCV000545380	likely benign	Hereditary diffuse gastric adenocarcinoma	2024-08-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221748	SCV001355151	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-19	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the +3 position of intron 4 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. However, functional study has shown there is no indication of an altered splicing (PMID: 23197654). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251178 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	RCV003226254	SCV003922929	uncertain significance	not specified	2023-03-03	criteria provided, single submitter	clinical testing	Variant summary: CDH1 c.531+3A>G alters a conserved nucleotide located close to a canonical 5' donor splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Two computational tools predict that the variant has a significant impact on normal splicing. However, a functional study has provided experimental evidence indicating that the variant does not affect splicing (Vogelaar_2013). The variant allele was found at a frequency of 4e-06 in 251178 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.531+3A>G has been reported in the literature in at least one individual affected with Lynch syndrome, however in this report the variant co-occurred with a pathogenic variant in an MMR gene, providing evidence supporting a benign role (Jori_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	RCV000461908	SCV003926663	uncertain significance	Hereditary diffuse gastric adenocarcinoma	2022-08-01	criteria provided, single submitter	clinical testing	PM2; BS3 (PMID: 30311375)