ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.687+2T>C

dbSNP: rs1555515297
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328402 SCV001244359 uncertain significance CDH1-related diffuse gastric and lobular breast cancer syndrome 2024-02-26 reviewed by expert panel curation The c.687+2T>C variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant is at +2 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). The variant has been observed in 6 individuals without DGC, SRC tumors or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting, BS2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp RCV000549831 SCV000637846 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-10-28 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 463790). Disruption of this splice site has been observed in individuals with diffuse gastric cancer (PMID: 15235021; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 5 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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).
Ambry Genetics RCV001025754 SCV001188004 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-07 criteria provided, single submitter clinical testing The c.687+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 5 in the CDH1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the ESEfinder and HSF splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

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