ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.335_337dup (p.Arg112dup) (rs768966657)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162477 SCV000212850 pathogenic Hereditary cancer-predisposing syndrome 2017-12-28 criteria provided, single submitter clinical testing The c.335_337dupGTC pathogenic mutation (also known as p.R112dup) located in coding exon 2 of the CDKN2A gene, results from an in-frame duplication of GTC between nucleotide positions 335 and 337. This results in the duplication of an extra arginine residue between codons 112 and 113. This alteration has been described as one of the most common CDKN2A mutations in Europe and as a founder mutation in the Swedish population, originating approximately 98 generations ago during Viking times (Borg et al. Cancer Res. 1996; 56(11): 2497-500; Goldstein AM et al. Cancer Res., 2006 Oct;66:9818-28;Goldstein AM. Hum. Mutat., 2004 Jun;23:630; Goldstein AM, J. Med. Genet. 2007 Feb; 44(2):99-106; Hashemi J, et al. Genes Chromosomes Cancer 2001 Jun; 31(2):107-16; Nielsen K et al. Melanoma Res., 2010 Aug;20:266-72; Helgadottir H et al. J. Natl. Cancer Inst., 2016 Nov;108:). This alteration is located in the functionally-important ankyrin repeat region and has been shown to result in loss of binding capacity for cdk4 and cdk6 in vitro (Ruas M, et al. Oncogene 1999 Sep; 18(39):5423-34; Borg A, J. Natl. Cancer Inst. 2000 Aug; 92(15):1260-6). Based on a study of 28 Swedish families with the c.335_337dupGTC mutation, carriers are estimated to have increased relative risk compared to non-carrier controls for melanoma (RR = 64.8) and pancreatic cancer (RR = 43.8), as well as malignancies of the upper digestive (RR = 17.1) and respiratory tract (RR = 15.6) (Helgadottir H, et al. J. Med. Genet. 2014 Aug; 51(8):545-52). Overall risks for these cancer types were increased further for ever-smoker carriers compared to never-smoker carriers in this study (OR = 9.3). Based on the available evidence, this alteration is classified as a pathogenic mutation. This mutation has also been reported as p.R112_L113insR, p.Arg105ins, 113insArg, and 337-338insGTC in published literature.
Invitae RCV000232355 SCV000283443 likely pathogenic Hereditary melanoma 2020-06-16 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 duplicates 3 nucleotides in exon 2 of the CDKN2A mRNA but otherwise preserves the integrity of the reading frame. This leads to the duplication of an arginine in the p16INK4a protein (p.Arg112dup). Alternatively, this leads to the duplication of a serine in the p14ARF protein (p.Ser127dup). This variant is present in population databases (rs768966657, ExAC 0.005%). This variant has been reported to segregate in affected individuals in numerous melanoma-prone families (PMID: 8653684, 24935963, 11319798, 25803691, 16905682, 27287845). Other cancers have also been found in individuals with this variant, including pancreatic cancer. It has been identified predominantly in melanoma patients with Swedish ancestry. Haplotype analysis suggest that this may be a common founder mutation (PMID:11319798, 8653684). This variant is also known as 113insR, 113insArg, p.R112_L113insR, and 112-113insArg in the literature. ClinVar contains an entry for this variant (Variation ID: 183759). Experimental studies have shown that p.Arg112dup in p16INK4a results in a loss-of-function. This sequence change decreased binding of the p16INK4a protein to the CDK4 and CDK6 proteins in vitro (PMID: 10922411). The functional impact of p.Ser127dup on p14ARF has not been tested. For these reasons, 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.
GeneDx RCV000237004 SCV000292539 pathogenic not provided 2018-12-31 criteria provided, single submitter clinical testing This in-frame duplication of 3 nucleotides in CDKN2A is denoted c.335_337dupGTC at the cDNA level and p.Arg112dup (R112dup) at the protein level. The normal sequence, with the bases that are duplicated in braces, is GGCC[GTC]TGCC. This duplication of a single Arginine residue occurs at a position that is conserved across species and is located in the 4th ANK repeat domain (UniProt). This variant has been identified in several malignant melanoma families and has been published as a Swedish founder pathogenic variant (Borg 1996, Platz1997, Borg 2000, Hashemi 2000, Hashemi 2001, Goldstein 2006, Helgadottir 2014). In vitro assays have shown that this variant lacks the ability to bind CDK4 and CDK6 (Ruas 1999, Borg 2000). We consider this variant to be pathogenic.
Color Health, Inc RCV000162477 SCV001349019 pathogenic Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing

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