ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.1147C>T (p.Gln383Ter)

dbSNP: rs587782798
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328234 SCV001142222 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-25 reviewed by expert panel curation The c.1147C>T (p.Gln383Ter) 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 23709761). 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 RCV000132351 SCV000187440 pathogenic Hereditary cancer-predisposing syndrome 2014-06-27 criteria provided, single submitter clinical testing The p.Q383* pathogenic mutation (also known as c.1147C>T), located in coding exon 9 of the CDH1 gene, results from a C to T substitution at nucleotide position 383. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation was observed in a French family with 3 cases of diffuse gastric cancer diagnosed at ages 24, 24, and 43, respectively (Benusiglio, PR et al. J Med Genet. 2013 Jul;50(7):486-9). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Fulgent Genetics, Fulgent Genetics RCV000763385 SCV000894085 pathogenic Familial cancer of breast; Blepharocheilodontic syndrome 1; Endometrial carcinoma; Hereditary diffuse gastric adenocarcinoma; Ovarian neoplasm; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000991081 SCV002239662 pathogenic Hereditary diffuse gastric adenocarcinoma 2021-04-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with diffuse gastric cancer (PMID: 23709761). ClinVar contains an entry for this variant (Variation ID: 142888). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln383*) 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).
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto RCV000991081 SCV003926747 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-08-01 criteria provided, single submitter clinical testing PVS1; PS4_Supporting; PM2 (PMID: 30311375)

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