Submissions for variant NM_000077.5(CDKN2A):c.335_337dup (p.Arg112dup)

dbSNP: rs768966657

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162477	SCV000212850	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-26	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 arginine residue at codon 112. This alteration has been described as one of the most common CDKN2A mutations in Europe and as a founder mutation in the Swedish population (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). Of note, this alteration is also known as p.R112_L113insR, p.Arg105ins, 113insArg, and 337-338insGTC in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232355	SCV000283443	pathogenic	Familial melanoma	2024-01-18	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 variant, c.335_337dup, results in the insertion of 1 amino acid(s) of the CDKN2A (p16INK4a) protein (p.Arg112dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768966657, gnomAD 0.003%). This variant has been observed in individuals with melanoma and/or pancreatic cancer (PMID: 8213823, 8653684, 11319798, 24935963, 30291219; Invitae). It is commonly reported in individuals of Swedish ancestry (PMID: 865368, 11319798). This variant is also known as 113insR, 113insArg, p.R112_L113insR, 112-113insArg, c.337_338insGTC in the CDKN2A (p16INK4a) transcript, and c.378_380dup (p.Ser127dup) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 183759). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CDKN2A (p16INK4a) function (PMID: 10922411). 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.
GeneDx	RCV000237004	SCV000292539	pathogenic	not provided	2022-07-21	criteria provided, single submitter	clinical testing	In-frame insertion of 1 amino acid located in the critical ANK 4 repeat (UniProt); Identified in several malignant melanoma families and published as a Swedish founder pathogenic variant (Borg et al., 1996; Platz et al., 1997; Borg et al., 2000; Hashemi et al., 2000; Hashemi et al., 2001; Goldstein et al., 2006; Helgadottir et al., 2014; Helgadottir et al., 2020); Case control studies suggest this variant is associated with increased risk for melanoma, pancreatic cancer, and possibly other cancers (Helgadottir et al., 2014); Published functional studies demonstrate a damaging effect: inability to bind CDK4 and CDK6 (Ruas et al., 1999; Borg et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 113insArg and c.337-338insGTC; This variant is associated with the following publications: (PMID: 10498896, 10922411, 9168184, 10338331, 16905682, 8653684, 24935963, 12072543, 17047042, 15146471, 19077144, 11319798, 11156381, 27287845, 29215650, 33076392, 33945383, 33766116, 30291219, 29922827)
Color Diagnostics, LLC DBA Color Health	RCV000162477	SCV001349019	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	clinical testing	This variant is a 3 nucleotide duplication located in exon 2 of the CDKN2A (p16INK4A) gene, creating a single amino acid duplication in the CDKN2A protein. Functional studies have shown that this variant impairs the binding to CDK4 and CDK6 in vitro (PMID: 10498896, 10922411). This variant has been reported in individuals affected with melanoma and is a frequently observed mutation in melanoma-prone families from Northern Europe (PMID: 8653684, 9168184, 10922411, 11156381, 11319798, 12072543, 16905682, 15146471, 17047042, 20526219, 24935963, 25803691, 25813228, 8653684, 9168184, 11319798). It has been shown that this variant segregates with disease and is reported as a Swedish founder mutation in melanoma-prone families (PMID: 8653684, 9168184, 11319798). Carrier families are also prone to non-melanoma cancer including breast and pancreatic carcinomas (PMID: 10922411, 15146471, 17047042, 24935963). This variant has been identified in 3/238418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics	RCV003474844	SCV004212529	pathogenic	Melanoma and neural system tumor syndrome	2022-07-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000237004	SCV004234501	pathogenic	not provided	2019-06-13	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000237004	SCV005199663	pathogenic	not provided	2023-10-05	criteria provided, single submitter	clinical testing