ClinVar Genomic variation as it relates to human health

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of CDK4/CDK6 binding, loss of cell cycle inhibitory activity, and altered subcellular localization (McKenzie 2010); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p16-Leiden and considered a Dutch founder variant; This variant is associated with the following publications: (PMID: 16905682, 29961768, 25227142, 12549483, 23897584, 10956390, 22636603, 9579547, 7640518, 26111702, 27406244, 11815963, 21570156, 12690301, 26670666, 27267843, 27672215, 18813118, 18981015, 15146471, 28592523, 29316957, 29263814, 29769629, 30113427, 31923587, 32953120, 32482799, 31203567, 20340136)

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.Ala76Cysfs*64) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 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 pancreatic cancer, cutaneous malignant melanoma, and familial atypical multiple mole melanoma (PMID: 7640518, 16905682, 17047042, 20340136, 22636603, 23897584, 109563903). It is commonly reported in individuals of Dutch ancestry (PMID: 7640518, 16905682, 17047042, 20340136, 22636603, 23897584, 109563903). This variant is also known as the p16-Leiden variant and c.268_286del (p.Arg90Valfs*76) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 182411). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CDKN2A (p16INK4a) function (PMID: 20340136). 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.225_243del19 pathogenic mutation, located in coding exon 2 of the CDKN2A gene, results from a deletion of 19 nucleotides at nucleotide positions 225 to 243, causing a translational frameshift with a predicted alternate stop codon (p.A76Cfs*64). This mutation has been reported in numerous individuals and families with personal and/or family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome (Gruis NA et al. Melanoma Res. 1995 Jun;5:169-77; Holland EA et al. Genes Chromosomes Cancer, 1999 Aug;25:339-48; Vasen HF et al. Int. J. Cancer, 2000 Sep;87:809-11; Goldstein AM. Hum. Mutat., 2004 Jun;23:630; Goldstein AM et al. J. Med. Genet., 2007 Feb;44:99-106; Harinck F et al. J. Med. Genet., 2012 Jun;49:362-5). Of note, this alteration is also designated as “p16-Leiden-mutation” in published literature, and has been described as a Dutch founder mutation. Functional analysis of this alteration revealed that transfected cells show altered subcellular localization, and significantly reduced binding affinity to CDK4 relative to wild type cells (McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701). The relative risk for pancreatic cancer associated with this specific alteration ranges from 17% (95% CI 3–30) to 47.8% (95% CI 28.4-74.7) (Vasen HF et al. Int. J. Cancer, 2000 Sep;87:809-11; de Snoo FA et al. Clin. Cancer Res. 2008 Nov;14:7151-7). Another study also found that smoking significantly increases risks of various cancers in carriers of this mutation (Potjer TP et al. Eur. J. Hum. Genet. 2015 May;23:711-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.

This variant deletes 19 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.

The CDKN2A c.225_243del19 variant is predicted to result in a frameshift and premature protein termination (p.Ala76Cysfs*64). It is also known as p16-Leiden, and reported as a Dutch founder variant. This variant has been reported in individuals with melanoma, and cancers of the pancreas and breast (Gruis et al. 1995. PubMed ID: 7640518; Koorstra et al. 2008. PubMed ID: 18813118; Li et al. 2018. PubMed ID: 29316957; Yurgelun et al. 2019. PubMed ID: 29961768). This variant has not been reported in a large population database and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/182411/). Frameshift variants in CDKN2A are expected to be pathogenic. This variant is interpreted as pathogenic.