Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000569093 | SCV000669189 | uncertain significance | Hereditary cancer-predisposing syndrome | 2017-08-16 | criteria provided, single submitter | clinical testing | The p.I49M variant (also known as c.147C>G), located in coding exon 1 of the CDKN2A gene, results from a C to G substitution at nucleotide position 147. The isoleucine at codon 49 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001217077 | SCV001388905 | uncertain significance | Familial melanoma | 2020-08-30 | criteria provided, single submitter | clinical testing | This variant disrupts the p.Ile49 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10719365, 10398427, 22841127, 20340136). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 483330). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with methionine at codon 49 of the CDKN2A (p16INK4a) protein (p.Ile49Met). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and methionine. |