ClinVar Genomic variation as it relates to human health

Non-canonical splice site variant demonstrated to result in aberrant splicing in a gene for which loss of function is a known mechanism of disease (Harland et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25685612, 16905682, 25780468, 26542317, 18612309, 22841127, 21614589, 21325014, 25023876, 11726555, 29215650, 23348723, 33322357, 15009729)

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant causes an A to G nucleotide substitution at the -105 position of intron 2 of the CDKN2A (p16INK4A) gene. This variant is also known as IVS2-105A>G in the literature. A non-quantitative RNA study has shown that this variant disrupts RNA splicing and causes aberrant retention of the entire, or almost all of, intron 2 sequence, resulting in the mutant transcripts that are much longer than the normal transcript (PMID: 11726555). This variant has been reported in over twenty individuals affected with familial cutaneous melanoma (PMID: 11726555, 15009729, 16905682, 22841127) and has been shown to segregate with disease in two families (PMID: 11726555). In addition, this variant has been observed to be de novo in an individual affected with multiple primary melanomas (PMID: 15009729). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

This sequence change falls in intron 2 of the CDKN2A (p16INK4a) gene. It does not directly change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cutaneous melanoma (PMID: 11726555, 15009729, 16905682, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2-105A>G. ClinVar contains an entry for this variant (Variation ID: 406715). Studies have shown that this variant results in inclusion of most or all of intron 2 in the CDKN2A (p16INK4a) mRNA and introduces a new termination codon (PMID: 11726555). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

The c.458-105A>G intronic variant results from an A to G substitution 105 nucleotides upstream from coding exon 3 in the CDKN2A gene. This alteration has been reported in multiple melanoma families and was shown to segregate with disease, although there were unaffected carriers in these families (ages unknown) (Harland M et al. Hum Mol Genet. 2001 Nov;10:2679-86; Goldstein AM et al. Genes Chromosomes Cancer. 2005 Jun;43(2):128-36; Maubec E et al. J Am Acad Dermatol 2012 Dec;67(6):1257-64; Puig S et al. Genet Med. 2016 Jul;18(7):727-36). This alteration was confirmed to be a de novo alteration in an individual with eight cutaneous melanomas (Majore S et al. J Invest Dermatol. 2004 Feb;122(2):450-1). This alteration was shown to generate two alternate transcripts that retain all or part of intron 2 which encodes a stop codon. Although it was not empirically shown, if these transcripts escape nonsense-mediated mRNA decay, the authors predict that protein product is likely to be structurally and functionally similar to the wildtype protein as they will only differ by four C-terminal amino acids (Harland M et al. Hum Mol Genet. 2001 Nov;10:2679-86). Of note, this variant is also designated as "IVS2-105A>G" in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as a disease-causing mutation.