ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.124_126delinsT (p.Pro42fs)

dbSNP: rs876658865
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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 RCV003328284 SCV001142265 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-29 reviewed by expert panel curation The c.124_126delCCCinsT (p.Pro42Serfs*16) 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://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 30745422). 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.
Ambry Genetics RCV000215517 SCV000274663 pathogenic Hereditary cancer-predisposing syndrome 2022-03-09 criteria provided, single submitter clinical testing The c.124_126delCCCinsT pathogenic mutation, located in coding exon 2 of the CDH1 gene, results from the deletion of 3 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.P42Sfs*16). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000991097 SCV001417924 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-08-30 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of hereditary diffuse gastric cancer syndrome (PMID: 30745422, 31296550). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro42Serfs*16) 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).
Myriad Genetics, Inc. RCV000991097 SCV004045146 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-08 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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