Submissions for variant NM_000077.5(CDKN2A):c.296G>A (p.Arg99Gln)

dbSNP: rs754806883

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000773061	SCV000906477	uncertain significance	Hereditary cancer-predisposing syndrome	2019-03-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000773061	SCV001178857	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The p.R99Q variant (also known as c.296G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 296. The arginine at codon 99 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in an individual with acute lymphoblastic leukemia; however, limited clinical information was provided (Xu H et al. Nat Commun, 2015 Jun;6:7553). This alteration was also identified in an individual diagnosed with breast cancer (Liu Y et al. Pathol Oncol Res, 2020 Jan;26:491-497). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001070305	SCV001235527	uncertain significance	Familial melanoma	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 99 of the CDKN2A (p16INK4a) protein (p.Arg99Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26104880). ClinVar contains an entry for this variant (Variation ID: 628568). 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 tolerated. This variant disrupts the p.Arg99 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425228, 17047042, 19260062, 20340316, 21462282, 22841127, 24660985). 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.
GeneDx	RCV001571416	SCV001795889	uncertain significance	not provided	2020-06-17	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer or leukemia (Xu 2015, Liu 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30634138, 9132280, 16354195, 30443844, 26104880)
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153831	SCV003843383	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing