Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000638996 | SCV000760554 | pathogenic | Familial melanoma | 2023-11-27 | 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 methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 53 of the CDKN2A (p16INK4a) protein (p.Met53Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 8595405, 9328469, 9389568, 9699728, 11595726, 16234564, 16307646, 16905682, 17171691, 25356972). This variant is also known as c.202G>A (p.Asp68Asn) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 532294). 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: 9328469, 9389568, 11595726). For these reasons, this variant has been classified as 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. |
| Ambry Genetics | RCV001012299 | SCV001172732 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-04-16 | criteria provided, single submitter | clinical testing | The p.M53I pathogenic mutation (also known as c.159G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 159. The methionine at codon 53 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with either multiple primary melanoma (MPM) or a single primary melanoma (SPM) (Begg CB et al. J. Natl. Cancer Inst., 2005 Oct;97:1507-15; Berwick M et al. Cancer Epidemiol. Biomarkers Prev., 2006 Aug;15:1520-5; Orlow I et al. J. Invest. Dermatol., 2007 May;127:1234-43; Ambry internal data). An alteration resulting in the same amino acid substitution, c.159G>C, is believed to be Scottish founder mutation and has been shown occur in and segregate with disease in multiple large melanoma kindreds (Lang J et al. Br. J. Dermatol., 2005 Dec;153:1121-5; Lang J et al. Genes Chromosomes Cancer, 2007 Mar;46:277-87; FitzGerald MG et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Aug;93:8541-5; Goldstein AM et al. J. Med. Genet., 2007 Feb;44:99-106; MacKie RM et al. J. Invest. Dermatol., 1998 Aug;111:269-72; Monzon et al. N Eng J Med 1998; 338(13): 879-87; Soufir N, et al. Hum. Mol. Genet. 1998 Feb;7(2):209-16; Walker GJ, Hum. Mol. Genet. 1995 Oct; 4(10):1845-52). Functional analyses of proteins harboring p.M53I substitution have demonstrated severely impaired CDK4 binding, reduced CDK6 binding, and reduced colony forming ability (Becker TM, et al. Clin. Cancer Res. 2001 Oct;7(10):3282-8; Harland M et al. Hum. Mol. Genet., 1997 Nov;6:2061-7; McKenzie et al. Hum Mutat 2010; 31(6): 692-701; Sun et al. Int J Cancer 1997; 73(4): 531-6). Based on internal structural analysis, p.M53I sits at the interface between alpha-helices and is anticipated to result in a significant decrease in structural stability and/or protein folding (Ambry internal data). Of note, this alteration is also designated as p.M45I in published literature. This amino acid position is well 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. |
| Color Diagnostics, |
RCV001012299 | SCV001736016 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-25 | criteria provided, single submitter | clinical testing | This missense variant replaces methionine with isoleucine at codon 53 outside of a highly conserved region of the ankyrin repeats 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 this variant to interfere with CDKN2A (p16INK4a) protein binding to CDK4 (PMID: 9328469, 9389568, 11595726) and result in the loss of cell cycle-inhibitory activity (PMID: 11595726). This variant has been reported in multiple individuals affected with melanoma (PMID: 16234564, 17171691, 31567591) and pancreatic cancer (PMID: 25356972, 32482799). A different nucleotide substitution resulting in the same protein consequence (c.159G>C, p.Met53Ile) is a common cause of melanoma in the Scottish (PMID: 17171691) and Norwegian populations (PMID 27804060). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. |
| Gene |
RCV002305521 | SCV002599881 | likely pathogenic | not provided | 2022-04-20 | criteria provided, single submitter | clinical testing | Observed in multiple individuals with melanoma or pancreatic cancer (Begg 2005, Berwick 2006, Orlow 2007, Zhen 2015, Overbeek 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11595726, 21462282, 32482799, 9328469, 16234564, 16896043, 17218939, 25356972) |
| Baylor Genetics | RCV003472005 | SCV004212534 | pathogenic | Melanoma and neural system tumor syndrome | 2022-03-22 | criteria provided, single submitter | clinical testing |