Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003328256 | SCV001244340 | likely benign | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-18 | reviewed by expert panel | curation | The c.69G>A (p.Glu23=) variant is absent from the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org). In silico splice site predictors do not suggest that this variant impacts splicing, and the G allele is not highly conserved across species (BP7).The variant has also been observed in >3 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2_Supporting; SCV000216307.4, SCV000545385.4, internal laboratory). Use of the Bayesian point system for this variant with conflicting evidence and classify this variant as likely benign. In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BP7, BS2_Supporting. |
| Ambry Genetics | RCV000165573 | SCV000216307 | likely benign | Hereditary cancer-predisposing syndrome | 2014-08-14 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Invitae | RCV000457649 | SCV000545385 | likely benign | Hereditary diffuse gastric adenocarcinoma | 2023-06-14 | criteria provided, single submitter | clinical testing | |
| Color Diagnostics, |
RCV000165573 | SCV000689561 | likely benign | Hereditary cancer-predisposing syndrome | 2017-01-10 | criteria provided, single submitter | clinical testing | |
| European Reference Network on Genetic Tumour Risk Syndromes |
RCV000457649 | SCV003926915 | likely benign | Hereditary diffuse gastric adenocarcinoma | 2022-08-01 | criteria provided, single submitter | clinical testing | PM2; BS2_Supporting; BP7 (PMID: 30311375) |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003398847 | SCV004121977 | likely benign | not specified | 2023-10-21 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV001355090 | SCV001549865 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The CDH1 p.Gln23= variant was identified in 1 of 808 proband chromosomes (frequency: 0.001) from individuals with a neurodevelopmental disorder (Kraemer 2019). The variant was identified in dbSNP (rs786202657) as “with uncertain significance allele” and ClinVar (classified as likely benign by Color and Ambry Genetics and uncertain significance by Invitae). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln23= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |