Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003328400 | SCV000864615 | pathogenic | CDH1-related diffuse gastric and lobular breast cancer syndrome | 2023-08-29 | reviewed by expert panel | curation | The c.283C>T (p.Gln95*) 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 2 families meeting HDGC clinical criteria (PS4_Moderate; PMID: 17545690, internal laboratory contributor). 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_Moderate, PM5_Supporting. |
Labcorp Genetics |
RCV000546548 | SCV000637817 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-12-02 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Gln95*) 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 present in population databases (rs781409616, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with gastric cancer and gastric, breast, and colon cancer (PMID: 11434599, 17545690, 21271559, 23709761, 26484312). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 463775). For these reasons, this variant has been classified as Pathogenic. |
Color Diagnostics, |
RCV001805167 | SCV002052264 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-06-07 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 3 of the CDH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with hereditary diffuse gastic cancer (HDGC) in the literature and was observed to co-segregate with HDGC in one family (PMID: 11434599, 17545690, 23709761). The variant has also been observed in breast and colorectal cancer cases (PMID: 21271559, 26484312). This variant has been identified in 1/251330 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
Ambry Genetics | RCV001805167 | SCV002752662 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-01-14 | criteria provided, single submitter | clinical testing | The p.Q95* pathogenic mutation (also known as c.283C>T), located in coding exon 3 of the CDH1 gene, results from a C to T substitution at nucleotide position 283. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This alteration has been reported in several hereditary diffuse gastric cancer and/or lobular breast cancer families (Dussaulx-Garin L et al. Eur J Gastroenterol Hepatol, 2001 Jun;13:711-5; Xie ZM et al. Cancer, 2011 Jul;117:3112-7; Benusiglio PR et al. J. Med. Genet., 2013 Jul;50:486-9). 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. |
European Reference Network on Genetic Tumour Risk Syndromes |
RCV000546548 | SCV003927014 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2022-08-01 | criteria provided, single submitter | clinical testing | PVS1; PS4_Moderate; PM2 (PMID: 30311375) |
Myriad Genetics, |
RCV000546548 | SCV004043344 | pathogenic | Hereditary diffuse gastric adenocarcinoma | 2023-06-08 | 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. |
Mayo Clinic Laboratories, |
RCV004791544 | SCV005414352 | pathogenic | not provided | 2024-05-17 | criteria provided, single submitter | clinical testing | PM2, PM5_supporting, PS4_moderate, PVS1 |