Submissions for variant NM_000077.5(CDKN2A):c.307_308del (p.Arg103fs)

dbSNP: rs886041162

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000348730	SCV000329239	pathogenic	not provided	2016-11-09	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in CDKN2A is denoted c.307_308delCG at the cDNA level and p.Arg103AlafsX16 (R103AfsX16) at the protein level. The normal sequence, with the bases that are deleted in braces, is GGCG[CG]GCTG. The deletion causes a frameshift which changes an Arginine to an Alanine at codon 103, and creates a premature stop codon at position 16 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. CDKN2A c.307_308delCG has been reported in a patient with multiple primary melanoma and functional yeast two-hybrid assay of this variant demonstrated significantly decreased binding activity to CDK4 in comparison to wild-type (Monzon 1998). We consider this variant to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001239756	SCV001412653	pathogenic	Familial melanoma	2019-11-19	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg103Alafs*16) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Alternatively, this sequence change results in a frameshift in the CDKN2A (p14ARF) gene (p.Ala117Glyfs*43). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acids of the CDKN2A (p14ARF) protein and extend the protein by an additional 26 amino acids. This variant has been observed in individual(s) with melanoma (PMID: 9516223, 17047042). ClinVar contains an entry for this variant (Variation ID: 279749). Experimental studies have shown that p.Arg103Alafs*16 in p16INK4a affects CDKN2A (p16INK4a) protein function (PMID: 9516223). The functional impact of p.Ala117Glyfs*43 in p14ARF has not been tested. 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. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682).