Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000457482 | SCV000545528 | likely pathogenic | Familial melanoma | 2024-12-12 | criteria provided, single submitter | clinical testing | 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. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 87 of the CDKN2A (p16INK4a) protein (p.Arg87Trp). This variant is present in population databases (rs749714198, gnomAD 0.003%). This missense change has been observed in individual(s) with familial melanoma (PMID: 10874641, 15860862, 18023021, 19260062, 21462282, 26650572, 26681309, 29774366). It has also been observed to segregate with disease in related individuals. This variant is also known as c.302C>T (p.Pro101Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 406707). 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: 19260062, 21462282, 23190892). This variant disrupts the p.Arg87 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7647780, 7987387, 8603820, 12352668). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic. In the absence of additional clinical evidence, this variant has been classified as Likely Pathogenic. While this evidence indicates that the variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, the association of this variant with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. |
| Gene |
RCV000481993 | SCV000568688 | likely pathogenic | not provided | 2023-06-21 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17370310, 21462282, 10874641, 21801156, 27804060, 25780468, 26650572, 25685612, 18023021, 26681309, 30218143, 35001868, Andreev2022[FunctionalStudy], 23190892, Jang2022[CaseReport], 19260062, 15860862, 31567591, 29774366, 33237286) |
| Color Diagnostics, |
RCV000580123 | SCV000684518 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-08-25 | criteria provided, single submitter | clinical testing | This missense variant replaces arginine with tryptophan at codon 87 in the ankyrin repeat 3 of the CDKN2A (p16INK4A) protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes a partial reduction in CDK4 binding (PMID: 19260062) and a significant loss of ability to control cell cycle (PMID: 19260062, 21462282, 23190892). This variant has been reported in at least twenty individuals affected with melanoma (PMID: 10874641, 15860862, 18023021, 19260062, 21462282, 21801156, 26650572) and in an unaffected individual (PMID: 26650572). This variant has been identified in 2/232208 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |
| ARUP Laboratories, |
RCV000481993 | SCV000883562 | likely pathogenic | not provided | 2017-10-12 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000988152 | SCV001137765 | likely pathogenic | Melanoma-pancreatic cancer syndrome | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV000580123 | SCV001176969 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-02-09 | criteria provided, single submitter | clinical testing | The p.R87W variant (also known as c.259C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 259. The arginine at codon 87 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with sporadic melanoma, multiple melanomas, and/or familial melanoma (Ambry internal data; Ruiz A et al. J Med Genet. 1999 Jun;36(6):490-3; Puig S et al. J Clin Oncol. 2005 May 1;23(13):3043-51; Helsing P et al. Genes Chromosomes Cancer. 2008 Feb;47(2):175-84; Cuellar F et al. Br J Dermatol. 2009 Jan;160(1):48-53; Kannengiesser C et al. Hum Mutat. 2009 Apr;30(4):564-74; Nikolaou V et al. Br J Dermatol. 2011 Dec;165(6):1219-22; Di Lorenzo S et al. Cancer Biol Ther. 2016;17(1):83-90; Li C et al. Melanoma Res 2020 06;30(3):247-251). Although a CDK4 binding assay showed only partial loss of CDK4 binding activity, a proliferation assay showed impaired capacity to inhibit proliferation of human diploid fibroblasts (Kannengiesser C et al. Hum Mutat. 2009 Apr;30(4):564-74). Additional functional assays have shown partial activity in a cell cycle arrest assay and impaired capacity to regulate both oxidative stress and cell cycle regulatory activity (Miller PJ et al. Hum Mutat. 2011 Aug;32(8):900-11; Jenkins NC et al. J Invest Dermatol. 2013 Apr;133(4):1043-51). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Baylor Genetics | RCV003476033 | SCV004212481 | likely pathogenic | Melanoma and neural system tumor syndrome | 2023-09-27 | criteria provided, single submitter | clinical testing |