Submissions for variant NM_000077.5(CDKN2A):c.79G>T (p.Glu27Ter)

dbSNP: rs1554656411

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541791	SCV000637430	pathogenic	Familial melanoma	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu27*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with two primary melanomas and melanoma (PMID: 16893909, 17047042, 18023021, 27804060). It is commonly reported in individuals of Italian ancestry (PMID: 16893909, 17047042, 18023021, 27804060). ClinVar contains an entry for this variant (Variation ID: 463512). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000657595	SCV000779334	pathogenic	not provided	2015-10-27	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted CDKN2A c.79G>T at the cDNA level and p.Glu27Ter (E27X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with melanoma and pancreatic cancer and was shown to result in significantly decreased p16 protein levels (Ghiorzo 2006, Ghiorzo 2012). We therefore consider this variant to be pathogenic.
Ambry Genetics	RCV001027038	SCV001189536	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-05	criteria provided, single submitter	clinical testing	The p.E27* pathogenic mutation (also known as c.79G>T), located in coding exon 1 of the CDKN2A gene, results from a G to T substitution at nucleotide position 79. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of the CDKN2A gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNA decay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653), however premature termination codons are typically deleterious in nature. This variant has been reported in familial melanoma kindreds and in apparently sporadic melanoma cases and is an Italian founder mutation (Ghiorzo P et al. Hum. Mol. Genet. 2006 Sep;15:2682-9). It has also been reported in patients with pancreatic cancer, including those from families with multiple cases of pancreatic cancer (Ghiorzo P et al. J. Med. Genet. 2012 Mar;49:164-70). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV001027038	SCV004361316	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-01	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 1 of the CDKN2A (p16INK4A) gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. The variant has been shown to significantly reduce p16 protein levels (PMID: 16893909). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 16893909, 17047042, 18024887, 18023021, 22368299, 27804060, 35777164), and has been shown to segregate with disease in melanoma kindreds (PMID: 16893909). Haplotype analysis has indicated that this variant is an Italian founder mutation (PMID: 16893909). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Baylor Genetics	RCV004568800	SCV005057262	pathogenic	Melanoma and neural system tumor syndrome	2023-12-11	criteria provided, single submitter	clinical testing