ClinVar Miner

Submissions for variant NM_004360.5(CDH1):c.60G>A (p.Trp20Ter)

dbSNP: rs786203576
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen CDH1 Variant Curation Expert Panel RCV003328261 SCV001142235 pathogenic CDH1-related diffuse gastric and lobular breast cancer syndrome 2023-08-29 reviewed by expert panel curation The c.60G>A (p.Trp20Ter) 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 two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 10072428, 28688938). 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.
Ambry Genetics RCV000166954 SCV000217775 pathogenic Hereditary cancer-predisposing syndrome 2023-09-20 criteria provided, single submitter clinical testing The p.W20* pathogenic mutation (also known as c.60G>A), located in coding exon 2 of the CDH1 gene, results from a G to A substitution at nucleotide position 60. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. A nonsense change occurring at the same amino acid position but at a different nucleotide position, p.W20* (c.59G>A), has been reported in one hereditary diffuse gastric cancer family (Richards FM et al. Hum. Mol. Genet. 1999 Apr; 8(4):607-10). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000991085 SCV002139404 pathogenic Hereditary diffuse gastric adenocarcinoma 2022-09-01 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: 187239). This premature translational stop signal has been observed in individual(s) with hereditary diffuse gastric cancer (PMID: 10072428, 28688938). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp20*) 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).
Myriad Genetics, Inc. RCV000991085 SCV004045043 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.

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