ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.489C>A (p.Cys163Ter)

dbSNP: rs1064794230
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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 RCV003328357 SCV001244348 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.489C>A (p.Cys163Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 26072394). 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 RCV000480530 SCV000568304 pathogenic not provided 2017-08-16 criteria provided, single submitter clinical testing This variant is denoted CDH1 c.489C>A at the cDNA level and p.Cys163Ter (C163X) at the protein level. The substitution creates a nonsense variant, which changes a Cysteine to a premature stop codon (TGC>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one individual with a personal history of diffuse gastric cancer and bilateral lobular breast cancer with a family history suggestive of Hereditary Diffuse Gastric Cancer (Kuijt 2012). It is considered pathogenic.
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV001078226 SCV003927046 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1; PS4_Supporting; PM2 (PMID: 30311375)
Labcorp Genetics (formerly Invitae), Labcorp RCV001078226 SCV005839045 pathogenic Hereditary diffuse gastric adenocarcinoma 2024-06-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Cys163*) 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 gastric and breast cancer (PMID: 22020549, 30745422, 34537906, 36436516). ClinVar contains an entry for this variant (Variation ID: 420004). For these reasons, this variant has been classified as Pathogenic.

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