Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003328344 | SCV001142263 | pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-30 | reviewed by expert panel | curation | The c.49-2A>G variant is a canonical splice variant predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1_Strong, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant was found to co-segregate with disease in multiple affected family members, with 3 meioses observed across at least two families (PP1; PMID: 17221870, 15780560). This variant has also been reported in at least three families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17221870, 15780560, 10072428). The c.49-2A>C allele was demonstrated to alter splicing through RT-PCR analysis of mRNA from an affected carrier (PS3_Moderate; PMID: 17221870). 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_Strong, PM2_Supporting, PP1, PS4_Moderate, PS3_Moderate, PM5_Supporting. |
Labcorp Genetics |
RCV000462976 | SCV000545400 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2022-02-09 | 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: 406631). Disruption of this splice site has been observed in individual(s) with diffuse gastric cancer, lobular breast cancer, and colorectal cancer (PMID: 10072428, 17221870). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). |
Ambry Genetics | RCV002339140 | SCV002642096 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-04-10 | criteria provided, single submitter | clinical testing | The c.49-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 2 in the CDH1 gene. This alteration was originally reported in a family with six individuals from two successive generations affected with diffuse gastric cancer (Richards FM et al. Hum. Mol. Genet., 1999 Apr;8:607-10). It has later been reported in another family with diffuse gastric cancer (Moran CJ et al. Eur J Surg Oncol, 2005 Apr;31:259-64), as well as in an individual with lobular breast cancer (McVeigh TP et al. Clin. Breast Cancer, 2014 Apr;14:e47-51). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. |
European Reference Network on Genetic Tumour Risk Syndromes |
RCV000462976 | SCV003926826 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2022-08-01 | criteria provided, single submitter | clinical testing | PVS1_Strong; PS3_Moderate; PS4; PM2; PP1 (PMID: 30311375) |
Myriad Genetics, |
RCV000462976 | SCV004043261 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-06-08 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15780560, 10072428, 24333020]. |
Baylor Genetics | RCV003476030 | SCV004210559 | pathogenic | Familial cancer of breast | 2022-10-05 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000462976 | SCV000033270 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 1999-04-01 | no assertion criteria provided | literature only |