Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003328154 | SCV001142244 | pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-29 | reviewed by expert panel | curation | The c.70G>T p.(Glu24Ter) 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: 10477433, 11104024). The variant was also found to co-segregate with disease in multiple affected family members, with 3 meioses observed (PP1; PMID: 10477433, 11104024). 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, PP1, PS4_Supporting, PM5_Supporting. |
| Labcorp Genetics |
RCV000013027 | SCV002242852 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-01-16 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu24*) 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). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12240). This premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (HDGC) (PMID: 10477433). It has also been observed to segregate with disease in related individuals. |
| Ambry Genetics | RCV002362580 | SCV002663119 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-04-19 | criteria provided, single submitter | clinical testing | The p.E24* pathogenic mutation (also known as c.70G>T), located in coding exon 2 of the CDH1 gene, results from a G to T substitution at nucleotide position 70. This changes the amino acid from a glutamic acid to a stop codon within coding exon 2. This mutation has been detected in two families with strong histories of diffuse gastric cancer as well as in an individual with signet ring cell carcinoma (Guilford PJ et al. Hum. Mutat., 1999;14:249-55; Lynch HT et al. Cancer, 2008 Jun;112:2655-63; Lee HE et al. Hum. Pathol., 2018 Jan;:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. |
| OMIM | RCV004579522 | SCV000033272 | pathogenic | DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME | 2000-10-01 | no assertion criteria provided | literature only |