ClinVar Genomic variation as it relates to human health

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Low nucleotide conservation. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families.

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PP1 strong

This variant occurs in a non-coding region of the CDKN2A (p16INK4a) gene. It does not change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with familial melanoma (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). It is commonly reported in individuals of British ancestry (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). ClinVar contains an entry for this variant (Variation ID: 182414). Studies have shown that this variant alters CDKN2A (p16INK4a) gene expression (PMID: 9916806, 20093296). For these reasons, this variant has been classified as Pathogenic.

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant is located in the 5' untranslated region of the CDKN2A gene (P16INK4A). A functional study has shown that this variant creates a new translation initiation AUG codon, and translation initiation from this novel site results in a truncated protein, while blocking wild-type protein expression (PMID: 9916806). This variant has been reported in over thirty individuals affected with melanoma (PMID: 9916806, 16397522, 17713569, 18025365, 19523171, 25023876, 25780468, 26581427, 26681309, 26775776, 29263814, 31567591) and has been shown to segregate with melanoma and pancreatic cancer in four different families (PMID: 9916806). This variant has been identified in 6/146754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

The c.-34G>T pathogenic mutation is located in the 5' untranslated region (5'UTR) of the CDKN2A gene. This mutation results from a G to T substitution 34 nucleotides upstream from the first translated codon. This sequence alteration creates a potential AUG initiation codon at base -35 and translation initiation from this novel start site predicts a truncated protein with no homology to wild type (Liu L et al. Nat. Genet. 1999 Jan;21:128-32). Functional studies demonstrate that the c.-34G>T mutation severely reduces the reporter activity in every cell type tested (Bisio A et al. Hum. Mol. Genet. 2010 Apr;19:1479-91). This alteration was identified in an individual with at least 3 primary melanoma diagnoses (Li C et al. Melanoma Res. 2020 06;30:247-251). In addition, this alteration has been reported in numerous families with melanoma, pancreatic cancer, and/or atypical nevi, and has been shown to segregate with disease (Liu L et al. Nat. Genet. 1999 Jan;21:128-32; Berwick M et al. Cancer Epidemiol. Biomarkers Prev. 2006 Aug;15:1520-5; Florell SR et al. J. Invest. Dermatol. 2008 Aug;128:2122-5; Larre Borges A et al. Br. J. Dermatol. 2009 Sep;161:536-41; Harland M et al. Hered. Cancer Clin. Pract. 2014 Nov;12:20; Bruno W et al. J. Am. Acad. Dermatol. 2016 Feb;74:325-32; Puig S et al. Genet. Med. 2016 Jul;18:727-36; Taylor NJ et al. J. Invest. Dermatol. 2017 12;137(12):2606-2612; Brand R et al. Cancer. 2018 Sep;124(17):3520-3527). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Describes a nucleotide substitution 34 base pairs upstream of the ATG translational start site of the CDKN2A gene that creates an aberrant ATG translation initiation codon; Published functional studies demonstrate a damaging effect: decreases translation from the wild-type ATG and results in a truncated protein that significantly affects reporter activity (PMID: 9916806, 20093296); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 26557774, 26775776, 19523171, 16896043, 25780468, 9916806, 20093296, 26581427, 26681309, 26099287, 12072543, 26681312, 16397522, 16905682, 15146471, 28495237, 29263814, 28830827, 30067863, 30117292, 30113427, 31567591, 33077847, 32482799, 34598035, 17713569, 29922827)

CDKN2A: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate

The CDKN2A c.-34G>T variant is located in the 5' untranslated region. This variant corresponds to a deep intronic position in the alternate transcript for this gene that encodes p14ARF (NM_058195.3:c.194-3653G>T). This variant has been reported in individuals with melanoma and segregated within families (Liu et al. 1999. PubMed ID: 9916806; Harland et al. 2000. PubMed ID: 10738302; Andreotti et al. 2016. PubMed ID: 26581427). It has also been reported in an individual with pancreatic adenocarcinoma (Brand et al. 2018. PubMed ID: 30067863). In vitro experimental studies indicate that this variant results in a novel alternative initiator that subsequently leads to decreased translation from the normal start site and ultimately a truncated protein (Liu et al. 1999. PubMed ID: 9916806). In addition, this variant significantly alters transcriptional activity as observed by in vitro reporter assay (Bisio et al. 2010. PubMed ID: 20093296). This variant is reported in 6 of ~147,000 alleles in gnomAD; however, the data quality is questionable and should be interpreted with caution. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/182414/). This variant is interpreted as pathogenic.