Submissions for variant NM_000077.5(CDKN2A):c.329G>A (p.Trp110Ter)

dbSNP: rs1057519852

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657726	SCV000779476	pathogenic	not provided	2017-06-29	criteria provided, single submitter	clinical testing	This variant is denoted CDKN2A c.329G>A at the cDNA level and p.Trp110Ter (W110X) at the protein level. The CDKN2A gene encodes the p16 protein, and using an alternate reading frame, the p14ARF protein as well. Although this variant is encoded in both proteins, the effect on the p14ARF protein is the synonymous change Leu124=. However, in regard to p16, the substitution creates a nonsense variant, which changes a Tryptophan to a premature stop codon (TGG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CDKN2A Trp110Ter has been shown to result in the absence of wild type p16 expression and lead to defective cell cycle arrest (Arap 1997, Krimpenfort 2001). Based on the currently available evidence, CDKN2A Trp110Ter is considered pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003584593	SCV004272096	pathogenic	Familial melanoma	2023-06-16	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. 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. ClinVar contains an entry for this variant (Variation ID: 376304). This variant is also known as c.372G>A (Silent) in CDKN2A (p14ARF) transcript. This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp110*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682).