ClinVar Genomic variation as it relates to human health

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 sequence change creates a premature translational stop signal (p.Pro81Cysfs*34) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 amino acid(s) of the CDKN2A (p16INK4a) protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with melanoma or pancreatic cancer (PMID: 7923152, 8710906, 15146471, 15173226, 21150883). It has also been observed to segregate with disease in related individuals. This variant is also known as c.238_251del in the CDKN2A (p16INK4a) transcript, and c.283_296del (p.Thr95Leufs*61) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 182412). This variant disrupts a region of the CDKN2A (p16INK4a) protein in which other variant(s) (p.Val126Asp) have been determined to be pathogenic (PMID: 7647780, 7987387, 8668202, 10389768, 11595726, 20340136, 23190892, 23371019). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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.

The c.240_253del14 pathogenic mutation, located in coding exon 2 of the CDKN2A gene, results from a deletion of 14 nucleotides at nucleotide positions 240 to 253, causing a translational frameshift with a predicted alternate stop codon (p.P81Cfs*34). This alteration has been described in multiple unrelated individuals with melanoma (FitzGerald MG et al. Proc Natl Acad Sci USA.1996;93(16):8541-5; Niendorf KB et al. J Med Genet. 2006;43:501-506; Goldstein AM et al. J Med Genet. 2007;44(2):99-106; Harland M et al. Hered Cancer Clin Pract 2014;12(1):20). It was also identified in a proband from an atypical malignant melanoma family. In addition to a personal and family history of melanoma, the proband had a history of cutaneous neurofibromas, papillary thyroid cancer, and uterine tumors (Vanneste R et al. Am. J. Med. Genet. A 2013 Jun;161A(6):1425-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

This variant deletes 14 nucleotides in exon 2 of the CDKN2A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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.

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.

The CDKN2A c.240_253del mutation has been reported previously in association with familial cutaneous malignant melanoma (Fitzgerald et al., 1996). The deletion causes a frameshift starting with codon Proline 81, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Pro81CysfsX34. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been observed to be inherited. The variant is found in CDKN2A panel(s).

Variant summary: CDKN2A c.240_253del14 (p.Pro81CysfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been found in other databases. The variant was absent in 231476 control chromosomes. c.240_253del14 has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma or other cancers. (FitzGerald_1996, Dudley_2018). These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.