ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.259C>T (p.Arg87Trp) (rs749714198)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000481993 SCV000883562 likely pathogenic not provided 2017-10-12 criteria provided, single submitter clinical testing
Color RCV000580123 SCV000684518 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-02 criteria provided, single submitter clinical testing
GeneDx RCV000481993 SCV000568688 likely pathogenic not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.259C>T at the cDNA level, p.Arg87Trp (R87W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been reported in multiple families and individuals with both single and multiple primary cutaneous malignant melanoma (Ruiz 1999, Puig 2005, Nikolaou 2011, Harland 2014, Di Lorenzo 2016, Levin 2016). Functional interrogation of CDKN2A Arg87Trp revealed a reduction in cell cycle arrest activity in comparison to wild type, a reduced oxidative regulatory function, and impaired interaction with CDK4 in vitro (Kannengiesser 2009, Miller 2013, Jenkins 2013). Another missense variant at the same codon, CDKN2A Arg87Pro (R87P), demonstrates loss-of-function with significantly impaired CDK4 binding and has been reported in association with familial cutaneous malignant melanoma and also in a family with a high incidence of head and neck squamous cell carcinoma and melanoma (Hussussian 1994, Parry 1996, Yu 2002). CDKN2A Arg87Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Arg87Trp occurs at a position that is conserved and is located in the ANK 3 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider CDKN2A Arg87Trp to be a likely pathogenic variant.
Invitae RCV000457482 SCV000545528 likely pathogenic Hereditary cutaneous melanoma 2018-12-31 criteria provided, single submitter clinical testing The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change replaces arginine with tryptophan at codon 87 of the CDKN2A (p16INK4a) protein (p.Arg87Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. Alternatively, this sequence change replaces proline with leucine at codon 101 of the CDKN2A (p14ARF) protein (p.Pro101Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs749714198, ExAC 0.002%). This variant has been reported in several individuals affected with familial melanoma (PMID: 10874641, 21462282, 15860862, 19260062, 26650572, 18023021, 26681309). ClinVar contains an entry for this variant (Variation ID: 406707). Experimental studies have shown that this missense change partially impairs the binding of the p16INK4a and CDK4 proteins, as well as the cell cycle and intracellular oxidative stress regulatory functions of p16INK4a (PMID: 21462282, 19260062, 23190892). The functional impact of p.Pro101Leu on the p14ARF protein has not been tested. A different missense substitution at this codon (p.Arg87Pro) of CDKN2A (p16INK4a) has been determined to be likely pathogenic (PMID: 7987387, 12352668, 8603820, 7647780). This suggests that the arginine residue is critical for CDKN2A (p16INK4a) protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been reported in affected individuals and has been shown to partially impair p16INK4a protein function. In the absence of additional data, this variant has been classified as Likely Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear.

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