Submissions for variant NM_000077.5(CDKN2A):c.172C>T (p.Arg58Ter)

dbSNP: rs121913387

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638957	SCV000760514	pathogenic	Familial melanoma	2019-11-16	criteria provided, single submitter	clinical testing	Loss-of-function variants in CDKN2A are known to be pathogenic (PMID: 15146471, 16905682). Experimental in vitro binding assays have shown that this variant disrupts the ability of p16INKA4a protein to bind to Cdk2 and Cdk4 (PMID: 8668202). An additional study in melanoma cells has shown that this variant reduces the ability of p14ARF to induce senescence and produce superoxide (PMID: 25370744). This variant has been observed in one individual and one family affected with melanoma (PMID: 18983535, 7987387). In addition, it has been reported to segregate with disease in that family (PMID: 7987387). This variant is also known as p16INK4a Arg50Ter in the literature. ClinVar contains an entry for this variant (Variation ID: 376310). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal at codon 58 of the p16INK4a protein (p.Arg58*). It is expected to result in an absent or disrupted p16INK4a protein product. Alternatively, this sequence gene replaces proline with leucine at codon 72 of the p14ARF protein. The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. 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.
Ambry Genetics	RCV002411285	SCV002716709	pathogenic	Hereditary cancer-predisposing syndrome	2017-07-20	criteria provided, single submitter	clinical testing	The p.R58* pathogenic mutation (also known as c.172C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 172. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation (also designated as "Arg50Ter" and "R58Ter") has been detected in multiple affected individuals from a familial melanoma kindred and shown to lack Cdk4 and Cdk6 binding in vitro (Hussussian CJ et al. Nat. Genet., 1994 Sep;8:15-21; Parry D et al. Mol. Cell. Biol., 1996 Jul;16:3844-52). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000638957	SCV004029842	pathogenic	Familial melanoma	2023-07-10	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.172C>T (p.Arg58X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 219734 control chromosomes (gnomAD). c.172C>T has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (e.g. Hussussian_1994). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 7987387). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Database of Curated Mutations (DoCM)	RCV000430418	SCV000505636	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Laboratory of Urology, Hospital Clinic de Barcelona	RCV003332170	SCV004040490	pathogenic	Malignant tumor of urinary bladder		no assertion criteria provided	research