ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.521dup (p.Asn174fs)

dbSNP: rs587781290
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328201 SCV001142215 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.521dupA p.(Asn174Lysfs) 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 two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17660459 and doi:10.1200/PO.16.00021). Therefore, 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_Moderate, PM5_Supporting.
Ambry Genetics RCV000128977 SCV000172863 pathogenic Hereditary cancer-predisposing syndrome 2022-05-23 criteria provided, single submitter clinical testing The c.521dupA pathogenic mutation, located in coding exon 4 of the CDH1 gene, results from a duplication of A at position 521, causing a translational frameshift with a predicted alternate stop codon (p.N174Kfs*25). This mutation has been reported in a woman with lobular breast cancer diagnosed at age 42 whose mother also developed lobular breast cancer at age 28. There were no other known breast or gastric cancers in the family (Masciari S et al. J Med Genet. 2007 Nov;44(11):726-31). It was also seen in two breast cancer patients who underwent multigene panel testing (Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). This mutation is also referred to as c.517insA in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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.
GeneDx RCV000479605 SCV000567906 pathogenic not provided 2021-05-17 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 24763289, 18046629, 17660459, 21271559, 26759166, 26182300, 20373070, 22524656, 22098830, 25186627, 26270727, 28152038, 29468433, 27720647, 29376063, 30745422)
Clinical Genetics and Genomics, Karolinska University Hospital RCV000479605 SCV001450214 pathogenic not provided 2017-03-17 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000991078 SCV002240085 pathogenic Hereditary diffuse gastric adenocarcinoma 2024-01-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn174Lysfs*25) 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 premature translational stop signal has been observed in individual(s) with lobular breast cancer (PMID: 17660459). ClinVar contains an entry for this variant (Variation ID: 140803). For these reasons, this variant has been classified as Pathogenic.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000991078 SCV003926662 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1; PS4_Moderate; PM2 (PMID: 30311375)
Myriad Genetics, Inc. RCV000991078 SCV004044099 pathogenic Hereditary diffuse gastric adenocarcinoma 2023-06-09 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
OMIM RCV000991078 SCV000033282 pathogenic Hereditary diffuse gastric adenocarcinoma 2007-11-01 no assertion criteria provided literature only

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