ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1137+2T>C

dbSNP: rs786202817
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328258 SCV001365458 likely pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-10-23 reviewed by expert panel curation This c.1137+2T>C variant occurs at the canonical donor splice site of exon 8 (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; http://gnomad.broadinstitute.org) and has been observed in at least one individual meeting IGCLC criteria for HDGC (PS4_supporting; internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting (Variant Interpretation Guidelines Version 3.1).
Ambry Genetics RCV000165833 SCV000216580 likely pathogenic Hereditary cancer-predisposing syndrome 2014-10-08 criteria provided, single submitter clinical testing The c.1137+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 8 in the CDH1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 45000 alleles tested) in our clinical cohort (includes this individual).This nucleotide position is highly conserved in available vertebrate species. Using the MaxEntScan, BDGP, and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.1137+2T>C variant is classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001195172 SCV001583048 pathogenic Hereditary diffuse gastric adenocarcinoma 2020-01-31 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Disruption of this splice site has been observed in individuals with diffuse gastric cancer (PMID: 10477433, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 186267). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies.
Color Diagnostics, LLC DBA Color Health RCV000165833 SCV001736335 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-26 criteria provided, single submitter clinical testing This variant causes a T to C nucleotide substitution at the canonical +2 position of intron 8 splice donor site of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 31296550). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same splice donor site c.1137+1G>A is known to be disease-causing (Clinvar variation ID: 233979). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

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