Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000584237 | SCV000689596 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-02-25 | criteria provided, single submitter | clinical testing | This missense variant replaces aspartic acid with tyrosine at codon 84 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has reported this variant to have no detectable binding to CDK4 and CDK6 in vitro (PMID: 10498896). This variant has been reported in an affected member of a Spanish cutaneous malignant melanoma family, however, segregation with two other affected members could not be examined (PMID: 10874641). The variant also has been detected in two affected members of a melanoma-prone family and at least two additional carriers whose cancer spectrum are not consistent with CDKN2A-associated cancers (Color internal data and communication with external laboratories). This variant has been identified in 1/231524 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Two different missense variants, p.Asp84Ala and p.Asp84Asn, have conflicting reports between likely pathogenic and uncertain significance in ClinVar (variation ID: 142882, 229806). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV000584237 | SCV001176643 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-12-20 | criteria provided, single submitter | clinical testing | The p.D84Y pathogenic mutation (also known as c.250G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 250. The aspartic acid at codon 84 is replaced by tyrosine, an amino acid with highly dissimilar properties. Functional studies demonstrate that this alteration results in impaired binding with CDK4 and CDK6 (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; Ruas M et al. Oncogene 1999 Sep;18(39):5423-34). Further, this alteration occurs at a mutational hotspot, with p.D84N and p.D84H also demonstrating impaired binding (Ruas M et al. Oncogene 1999 Sep;18(39):5423-34). Structural analysis indicates that this alteration dramatically alters the electrostatic character of the CDK-binding surface of p16, resulting in a severe pertubation of the protein structure which likely leads to misfolding and loss of binding (Ruas M et al. Oncogene 1999 Sep;18(39):5423-34; Rajasekaran R et al. Biochimie 2008 Oct;90(10):1523-9; Ambry internal data). In addition, this alteration has been reported in multiple families with familial melanoma, including one family with three individuals with cutaneous malignant melanoma and two individuals with dysplastic nevi (Ambry internal data; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11; Ruiz A et al. J. Med. Genet. 1999 Jun;36(6):490-3). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Labcorp Genetics |
RCV001239054 | SCV001411899 | uncertain significance | Familial melanoma | 2023-08-22 | criteria provided, single submitter | clinical testing | The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 10360174, 10498896). 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. ClinVar contains an entry for this variant (Variation ID: 376306). This variant is also known as c.293G>T (p.Arg98Leu) in the CDKN2A (p14AFR) transcript. This missense change has been observed in individual(s) with melanoma (PMID: 10874641, 21462282, 26650189, 26681309). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 84 of the CDKN2A (p16INK4a) protein (p.Asp84Tyr). The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. |
| Database of Curated Mutations |
RCV000419046 | SCV000505632 | likely pathogenic | Neoplasm | 2015-07-14 | no assertion criteria provided | literature only |