Submissions for variant NM_000077.5(CDKN2A):c.301G>C (p.Gly101Arg)

dbSNP: rs104894094

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196728	SCV000254240	uncertain significance	Familial melanoma	2024-06-24	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 glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 101 of the CDKN2A (p16INK4a) protein (p.Gly101Arg). This variant is present in population databases (rs104894094, gnomAD 0.003%). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 21801156, 25356972, 29774366). This variant is also known as c.344G>C (p.Arg115Pro) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 216274). 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 does not substantially affect CDKN2A (p16INK4a) function (PMID: 12606942, 21462282, 35001868). This variant disrupts the p.Gly101 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10869234, 11807902, 14679123, 15146471, 21462282, 21801156). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000216848	SCV000278631	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-18	criteria provided, single submitter	clinical testing	The p.G101R variant (also known as c.301G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 301. The glycine at codon 101 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in a Greek proband with a personal and family history of melanoma (Nikolaou V et al, Br. J. Dermatol. 2011 Dec; 165(6):1219-22), in three patients with multiple primary melanomas from a cohort of 587 patients with either multiple- or single-primary melanomas from Italy (Bruno W et al. J Am Acad Dermatol, 2016 Feb;74:325-32), and in a cohort of 296 breast cancer patients from India who were tested with a 30-gene panel (Kaur RP et al. Med Oncol, 2018 Apr;35:81). Functional studies have shown this alteration exhibits cell cycle arrest activity similar to wildtype (Greenblatt MS et al. Oncogene, 2003 Feb;22:1150-63; Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000587052	SCV000566707	uncertain significance	not provided	2015-06-03	criteria provided, single submitter	clinical testing	This variant is denoted CDKN2A c.301G>C at the cDNA level, p.Gly101Arg (G101R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>CGG). This variant was observed in a case of familial melanoma (Nikolaou 2011). An alternate base change, CDKN2A c.301G>A, which leads to the same amino acid change observed in this case, Gly101Arg, has been observed in a familial pancreatic cancer family, and was found in functional assays to behave similar to wild-type with regard to cell-cycle arrest and loss of function (Miller 2011, Zhen 2014, Greenblatt 2003). CDKN2A Gly101Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A Gly101Arg occurs at a position that is conserved in mammals, with Arginine being the naturally occurring amino acid at this position in one vertebrate, and is located in the ANK 3 repeat (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDKN2A Gly101Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587052	SCV000695340	uncertain significance	not provided	2016-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216848	SCV000906448	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF ( https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces glycine with arginine at codon 101 of the CDKN2A (p16INK4A) protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). However, functional studies have shown that this variant induces cell cycle arrest similarly to wild-type p16INK4a protein (PMID: 12606942, 21462282). This variant has been reported in at least one individual affected with single primary melanoma (PMID: 21801156, 29774366), in an individual affected with pancreatic cancer (PMID: 25356972), and in 3 individuals affected with multiple primary melanoma (PMID: 26775776). This variant has been identified in 2/234468 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same position, p.Gly101Trp, is known to be pathogenic (Clinvar variation ID: 9412), indicating glycine at this position is important for the p16INK4a protein function. Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV004567423	SCV005057243	uncertain significance	Melanoma and neural system tumor syndrome	2024-02-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV005230069	SCV005873427	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing