Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003328233 | SCV001365431 | pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-25 | reviewed by expert panel | curation | The c.1921C>T p.(Gln641Ter) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_supporting). The variant is present in <1/100,000 alleles 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; SCV000187340.5). 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 | RCV000132257 | SCV000187340 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-06-22 | criteria provided, single submitter | clinical testing | The p.Q641* pathogenic mutation (also known as c.1921C>T), located in coding exon 12 of the CDH1 gene, results from a C to T substitution at nucleotide position 1921. This changes the amino acid from a glutamine to a stop codon within coding exon 12. 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. |
Counsyl | RCV000662630 | SCV000785306 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2017-07-07 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000662630 | SCV001584184 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2022-12-16 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 142826). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (rs587782750, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln641*) 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). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000662630 | SCV002548319 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2022-05-03 | criteria provided, single submitter | clinical testing | Variant summary: CDH1 c.1921C>T (p.Gln641X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251462 control chromosomes. c.1921C>T has been reported in the literature in individuals affected with CDH1-related cancers such as Gastric and Lobular Breast Cancer (example, LaDuca_2017, Lowstuter_2017, Xicola_2019, Gao_2021). Three clinical diagnostic laboratories and an expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Myriad Genetics, |
RCV000662630 | SCV004020027 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-03-06 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |