Submissions for variant NM_000077.5(CDKN2A):c.44_46dup (p.Trp15_Leu16insArg)

dbSNP: rs730881672

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160402	SCV000210934	pathogenic	Hereditary cancer-predisposing syndrome	2014-02-10	criteria provided, single submitter	clinical testing	The CDKN2A c.46_47insGGC mutation results in the insertion of a single amino acid, Arginine, between codons Tryptophan 15 and Leucine 16. This variant is denoted at the protein level as p.Trp15_Leu16insArg (W15_L16insR). It is located within the ANK1 repeat of the CDKN2A gene. This mutation has not been previously reported to our knowledge. However, a nearby in-frame duplication within the ANK1 repeat, c.52_57dup6, has been reported as a mutation (Soufir 1998, Goldstein 2007) and shown to be deficient for CDK4 binding (Kannengiesser 2009). In addition, missense substitutions at Leucine 16, L16P and L16R, have been published as mutations (Soufir 1998, Goldstein 2000).This variant has been observed to be inherited. The variant is found in CDKN2A,CDKN2A panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002515113	SCV003006068	uncertain significance	Familial melanoma	2023-07-10	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 182408). 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 variant, c.44_46dup, results in the insertion of 1 amino acid(s) of the CDKN2A (p16INK4a) protein (p.Trp15_Leu16insArg), but otherwise preserves the integrity of the reading frame. 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.