Submissions for variant NM_000077.5(CDKN2A):c.175G>A (p.Val59Met)

dbSNP: rs1819723898

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001305143	SCV001494462	uncertain significance	Familial melanoma	2024-09-21	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 valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 59 of the CDKN2A (p16INK4a) protein (p.Val59Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.218G>A (p.Ser73Asn) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 1007891). 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.Val59 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9425228, 12700603, 15146471, 19799798, 21893440, 22841127). 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	RCV002402852	SCV002714369	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	The p.V59M variant (also known as c.175G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 175. The valine at codon 59 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is 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.
Martignetti Lab, Icahn School of Medicine at Mount Sinai	RCV003327300	SCV004034089	association	Atypical endometrial hyperplasia		no assertion criteria provided	research