ClinVar Genomic variation as it relates to human health

Observed in numerous individuals of various ethnicities with a personal and/or family history of melanoma and identified as a founder variant in the Scottish population (Walker 1995, MacKie 1998, Tsao 2000, Box 2001, Goldstein 2004, Lang 2005, Kannengiesser 2007, Lang 2007, Helsing 2008, Harland 2014, Sinnya 2015); Published functional studies demonstrate a damaging effect: significantly reduced binding to CDK4 compared to wild-type (Sun 1997, Monzon 1998, Becker 2001, McKenzie 2010); 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: 17171691, 10987867, 10861313, 16905682, 27804060, 27568332, 31653154, 17713569, 29922827, 20340136, 17492760, 11595726, 9516223, 15146471, 21507037, 18023021, 25780468, 9603434, 9416844, 15173226, 22841127, 12459645, 9389568, 8710906, 1531137, 7083179, 8595405, 26681309, 9699728, 11500805, 16307646, 26103950, 25370744, 16354195, 31567591, 32427313)

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces methionine with isoleucine at codon 53 of the CDKN2A (p16INK4A) protein. Computational prediction tool 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 reported defects in CDK binding, loss of cell cycle control and inhibition of cellular growth (PMID: 9328469, 9389568, 11595726, 20340136). This variant has been reported as a Scottish melanoma founder mutation (PMID 17171691) and observed in melanoma affected families in Europe, North America, and Australia (PMID 8595405, 9328469, 9389568, 9699728, 16234564, 16307646, 16896043, 16905682) and in individual(s) with pancreatic cancer with positive family history (PMID 25356972, 32482799). This variant has been identified in 2/221078 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A (p16INK4A) function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.

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 present in population databases (rs104894095, gnomAD 0.008%). This missense change has been observed in individual(s) with melanoma (PMID: 8595405, 9328469, 9699728, 16307646, 16905682, 17171691). It is commonly reported in individuals of Scottish ancestry (PMID: 8595405, 9328469, 9699728, 16307646, 16905682, 17171691). This variant is also known as c.202G>C (p.Asp68His) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9414). 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.

The p.M53I pathogenic mutation (also known as c.159G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 159. The methionine at codon 53 is replaced by isoleucine, an amino acid with highly similar properties. This mutation has been identified in many familial melanoma kindreds and has also been shown to segregate with disease multiple large families (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; Flores JF et al. Oncogene 1997 Dec;15(24):2999-3005). In a Norwegian study, it was identified in multiple probands with melanoma and pancreatic cancer (Levin T and Maehle L Fam. Cancer. 2017 04;16(2):257-265). Functional analyses of proteins harboring the p.M53I substitution have consistently demonstrated impaired binding to CDK4. In some cases, the variant protein was also shown to have reduced association with CDK6 and/or impaired growth and colony formation (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; Walker et al. Int J Cancer 1999; 82(2): 305-12). Of note, this alteration is also designated as p.M45I in published literature. Haplotype analysis strongly suggests that the p.M53I mutation is likely a founder mutation, originating in Scotland (Lang J et al. Br. J. Dermatol., 2005 Dec;153:1121-5; Lang J et al. Genes Chromosomes Cancer, 2007 Mar;46:277-87). Based on the available evidence, this alteration is classified as a pathogenic mutation.

The CDKN2A c.159G>C variant is predicted to result in the amino acid substitution p.Met53Ile. This variant was reported in several individuals with melanoma and in one individual with pancreatic cancer (Table 2. Li et al. 2020. PubMed ID: 31567591; Table 2. Hubert et al. 2021. PubMed ID: 34067022; Table 1, Figure 1b. Flores et al. 1997. PubMed ID: 9416844; Lang et al. 2005. PubMed ID: 16307646; Table 2. FitzGerald et al. 1996. PubMed ID: 8710906; Figure 1. Begg et al. 2005. PubMed ID: 16234564; Table 2. Zhen et al. 2014. PubMed ID: 25356972). In vitro experimental studies show this amino acid change impacts protein function (McKenzie et al. 2010. PubMed ID: 20340136; Figure 3. Monzon et al. 1998. PubMed ID: 9516223). This variant is reported in 0.0075% of alleles in individuals of African descent in gnomAD and is classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9414/). This variant is interpreted as pathogenic.