Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003328457 | SCV001142234 | pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2024-03-25 | reviewed by expert panel | curation | The c.687+1G>A is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong, PM5_Supporting). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in three families meeting IGCLC criteria for HDGC (PS4_Moderate; PMID: 15235021 and 30306390, SCV000815329.1). The variant was also found to co-segregate with HDGC in a family with HDGC and cleft lip/palete (PP1_Supporting; PMID: 30306390). RNA analysis demonstrated an in-frame deletion of 14 amino acids from exon 5, r.646_687del p.(V216_T229del) (PS3_Supporting; PMID: 30306390 and internal laboratory data). 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, PS3_Supporting, PM2_Supporting, PS4_Moderate, PM5_Supporting and PP1_Supporting. |
Labcorp Genetics |
RCV000687744 | SCV000815329 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2018-02-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants 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). This variant has been reported in individuals affected with diffuse gastric cancer who also had a family history of gastric cancer and/or lobular breast cancer (PMID: 15235021, Invitae). This variant is also known as IVS5(+1) G>A in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. |
Ambry Genetics | RCV001025753 | SCV001188003 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-10-28 | criteria provided, single submitter | clinical testing | The c.687+1G>A pathogenic mutation results from a G to A substitution one nucleotide after coding exon 5 of the CDH1 gene. This pathogenic mutation has been detected in two families meeting clinical criteria for hereditary diffuse gastric cancer (Obermair F et al. Fam. Cancer, 2019 04;18:253-260, Brooks-Wilson AR et al. J. Med. Genet., 2004 Jul;41:508-17). RNA analyses have shown that this mutation abolishes the native donor site, resulting in an abnormal transcript with 42 nucleotides deleted from exon 5 (Obermair F et al. Fam. Cancer, 2019 04;18:253-260; Ambry internal data). Another mutation at this position (c.687+1G>C) was reported in a proband with a family history of diffuse gastric cancer (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Myriad Genetics, |
RCV000687744 | SCV004045012 | likely pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-06-09 | 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. |