ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1587dup (p.Ala530fs)

dbSNP: rs1555516532
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328366 SCV001437618 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.1587dup (p.Ala530fs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). This variant has been identified in a family meeting HDGC clinical criteria (PS4_Supporting; SCV000580697.3). In summary, this variant meets criteria to be classified as Pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting.
GeneDx RCV000478712 SCV000572036 pathogenic not provided 2016-10-13 criteria provided, single submitter clinical testing This duplication of one nucleotide in CDH1 is denoted c.1587dupT at the cDNA level and p.Ala530CysfsX7 (A530CfsX7) at the protein level. The normal sequence, with the base that is duplicated in braces, is ACAC[T]GCCA. The duplication causes a frameshift which changes an Alanine to a Cysteine at codon 530, and creates a premature stop codon at position 7 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, an adjacent variant CDH1 c.1588insC which causes a similar frameshift has been reported in a diffuse gastric cancer kindred (Guilford 1999). Based on the currently available information, we consider CDH1 c.1587dupT to be pathogenic.
Ambry Genetics RCV000492449 SCV000580697 pathogenic Hereditary cancer-predisposing syndrome 2021-06-25 criteria provided, single submitter clinical testing The c.1587dupT pathogenic mutation, located in coding exon 11 of the CDH1 gene, results from a duplication of T at nucleotide position 1587, causing a translational frameshift with a predicted alternate stop codon (p.A530Cfs*7). This alteration has been observed in at least two families with a history that is consistent with CDH1-related disease (Ambry internal data). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478712 SCV001469484 likely pathogenic not provided 2020-02-25 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Not found in the total gnomAD dataset, and the data is high quality.
Labcorp Genetics (formerly Invitae), Labcorp RCV001260575 SCV002243027 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-10-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala530Cysfs*7) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). 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: 422539). For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc. RCV001260575 SCV004044095 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-14 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

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