Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000206296 | SCV000261483 | pathogenic | Familial melanoma | 2023-05-15 | criteria provided, single submitter | clinical testing | 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: 220711). This variant is also known as 50Q>X. This premature translational stop signal has been observed in individual(s) with pancreatic cancer and melanoma (PMID: 12454511, 18983535, 25356972, 25877891). This sequence change creates a premature translational stop signal (p.Gln50*) 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). |
| Ambry Genetics | RCV000221580 | SCV000275624 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-04-26 | criteria provided, single submitter | clinical testing | The p.Q50* pathogenic mutation (also known as c.148C>T), located in coding exon 1 of the CDKN2A gene, results from a C to T substitution at nucleotide position 148. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This pathogenic variant has been identified in numerous individuals from melanoma and pancreatic cancer cohorts (Bartsch DK et al. Ann. Surg. 2002 Dec;236:730-7; Pastorino L et al. Pigment Cell Melanoma Res. 2008 Dec;21:700-9; Zhen DB et al. Genet. Med. 2015 Jul;17:569-77). The p.Q50* pathogenic mutation has also shown an inability to bind to Cdk4 and Cdk6 when assessed in vitro (Parry D et al. Mol. Cell. Biol. 1996 Jul;16:3844-52). 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. |
| Gene |
RCV000485187 | SCV000568689 | pathogenic | not provided | 2016-05-23 | criteria provided, single submitter | clinical testing | This variant is denoted CDKN2A c.148C>T at the cDNA level and p.Gln50Ter (Q50X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Consistent with predictions, Parry et al (1996) demonstrated via Cdk binding assays that this variant results in a truncated protein that is unable to bind to CDK2, CDK4, or CDK6. This variant has been reported in an individual with pancreatic cancer and her father with melanoma, and was also observed in at least one individual with multiple primary melanomas (Bartsch 2002, Pastorino 2008). Based on currently available evidence, we consider this variant pathogenic. |
| Baylor Genetics | RCV003474986 | SCV004212522 | pathogenic | Melanoma and neural system tumor syndrome | 2023-02-08 | criteria provided, single submitter | clinical testing |