Submissions for variant NM_058195.4(CDKN2A):c.160C>A (p.Arg54Ser)

gnomAD frequency: 0.00006  dbSNP: rs896054565

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000571273	SCV000676315	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The p.R54S variant (also known as c.160C>A), located in coding exon 1 of the CDKN2A gene, results from a C to A substitution at nucleotide position 160. The arginine at codon 54 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702275	SCV000831122	uncertain significance	Familial melanoma	2021-09-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with serine at codon 54 of the CDKN2A (p14ARF) protein (p.Arg54Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p14ARF)-related conditions. ClinVar contains an entry for this variant (Variation ID: 487012). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C35". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Mendelics	RCV000709076	SCV000838336	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 2	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001569842	SCV001793999	uncertain significance	not provided	2024-08-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported using an alternate transcript of the gene; This variant is associated with the following publications: (PMID: 37529773, 9653180, 9529249, 16173922, 35264596)
Baylor Genetics	RCV004568233	SCV005057246	uncertain significance	Melanoma and neural system tumor syndrome	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004754479	SCV005363526	uncertain significance	CDKN2A-related disorder	2024-08-01	no assertion criteria provided	clinical testing	The CDKN2A c.160C>A variant is predicted to result in the amino acid substitution p.Arg54Ser. This variant was reported as a variant of uncertain significance in an individual with pheochromocytoma and paragangliomas (Supplementary Table 1. Lima et al. 2023. PubMed ID: 37529773). The variant is also reported as c.-19345C>A, which is predicted to result in a pre-coding effect (NM_0000177.4). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD and is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/487012/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.