Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000167463 | SCV000218319 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-10 | criteria provided, single submitter | clinical testing | The p.Q50P variant (also known as c.149A>C), located in coding exon 1 of the CDKN2A gene, results from an A to C substitution at nucleotide position 149. The glutamine at codon 50 is replaced by proline, an amino acid with similar properties. This alteration was initially reported in a melanoma and pancreatic cancer kindred. The proband was diagnosed with melanoma at age 29y and had three first-degree relatives (FDRs) with melanoma as well as one FDR and one second-degree relative (SDR) with pancreatic cancer (Lynch HT, Cancer 2002 Jan; 94(1):84-96). This alteration has also been reported in a proband with melanoma who had a family history of melanoma in 2/7 FDRs (Begg CB, J. Natl. Cancer Inst. 2005 Oct; 97(20):1507-15). RT-PCR of RNA extracted from lymphoblastoid cells showed an incomplete splicing impact for this alteration, predicted to result in a protein with an in-frame deletion of 23 amino acids (Loo JC, Oncogene 2003 Sep; 22(41):6387-94). In addition, a yeast-based assay reported that this alteration impaired binding with CDK4 (Loo JC, Oncogene 2003 Sep; 22(41):6387-94). Another alteration at the same codon, p.Q50R (c.149A>G), has been detected in melanoma and pancreatic cancer cohorts and was reported to segregate with melanoma in at least six melanoma-affected individuals in one family (Walker GJ et al. Hum. Mol. Genet. 1995 Oct;4:1845-52; Box NF et al. Am. J. Hum. Genet. 2001 Oct;69:765-73). This amino acid position is highly conserved in available vertebrate species. In addition, this missense alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Labcorp Genetics |
RCV001220072 | SCV001392045 | likely pathogenic | Familial melanoma | 2023-08-30 | criteria provided, single submitter | clinical testing | This missense change has been observed in individual(s) with melanoma (PMID: 11815963, 16234564, 16896043, 30967399). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 50 of the CDKN2A (p16INK4a) protein (p.Gln50Pro). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 187713). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 14508519). Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 14508519). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |