Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000563258 | SCV000669208 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-08-26 | criteria provided, single submitter | clinical testing | The p.M1? variant (also known as c.2T>C), located in coding exon 1 of the CDKN2A gene, results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon. Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an alternate in-frame methionine nine amino acids from the initiation site and the significance of the N-terminus for this protein is not well established. This alteration has been detected in one individual affected with melanoma, in the absence of a family history of melanoma (Ghiorzo P et al. Exp. Dermatol., 2012 Sep;21:718-20). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5443 samples (10886 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 75000 alleles tested) in our clinical cohort. This amino acid position is not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001858285 | SCV002192419 | uncertain significance | Familial melanoma | 2023-03-17 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 483341). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the CDKN2A (p16INK4a) mRNA. The next in-frame methionine is located at codon 9. |