Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000541791 | SCV000637430 | pathogenic | Familial melanoma | 2023-08-02 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 463512). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with two primary melanomas and melanoma (PMID: 16893909, 17047042, 18023021, 27804060). It is commonly reported in individuals of Italian ancestry (PMID: 16893909, 17047042, 18023021, 27804060). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu27*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). |
| Gene |
RCV000657595 | SCV000779334 | pathogenic | not provided | 2015-10-27 | criteria provided, single submitter | clinical testing | This pathogenic variant is denoted CDKN2A c.79G>T at the cDNA level and p.Glu27Ter (E27X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with melanoma and pancreatic cancer and was shown to result in significantly decreased p16 protein levels (Ghiorzo 2006, Ghiorzo 2012). We therefore consider this variant to be pathogenic. |
| Ambry Genetics | RCV001027038 | SCV001189536 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-11-25 | criteria provided, single submitter | clinical testing | The p.E27* variant (also known as c.79G>T), located in coding exon 1 of the CDKN2A gene, results from a G to T substitution at nucleotide position 79. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This variant has been reported in familial melanoma kindreds and in apparently sporadic melanoma cases and is an Italian founder mutation (Ghiorzo P et al. Hum. Mol. Genet. 2006 Sep;15:2682-9). It has also been reported in patients with pancreatic cancer, including those from families with multiple cases of pancreatic cancer (Ghiorzo P et al. J. Med. Genet. 2012 Mar;49:164-70). 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. |
| Color Diagnostics, |
RCV001027038 | SCV004361316 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-01 | criteria provided, single submitter | clinical testing | This variant changes 1 nucleotide in exon 1 of the CDKN2A (p16INK4A) gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. The variant has been shown to significantly reduce p16 protein levels (PMID: 16893909). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 16893909, 17047042, 18024887, 18023021, 22368299, 27804060, 35777164), and has been shown to segregate with disease in melanoma kindreds (PMID: 16893909). Haplotype analysis has indicated that this variant is an Italian founder mutation (PMID: 16893909). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
| Baylor Genetics | RCV004568800 | SCV005057262 | pathogenic | Melanoma and neural system tumor syndrome | 2023-12-11 | criteria provided, single submitter | clinical testing |