Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002323583 | SCV002607223 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-09-13 | criteria provided, single submitter | clinical testing | The p.W110* variant (also known as c.330G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 330. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This alteration has been detected in several melanoma patients, including a Greek patient diagnosed with multiple primary melanomas (Stratigos AJ et al. J Invest Dermatol. 2006 Feb;126:399-401; Nikolaou V et al. Br J Dermatol. 2011 Dec;165:1219-22; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration demonstrated reduced Cdk binding activity (Parry D et al. Mol Cell Biol. 1996 Jul;16:3844-52). 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. |
| Labcorp Genetics |
RCV002524693 | SCV003440778 | pathogenic | Familial melanoma | 2023-05-03 | criteria provided, single submitter | clinical testing | 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. Experimental studies have shown that this premature translational stop signal affects CDKN2A (p16INK4a) function (PMID: 8668202). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 376303). This variant is also known as c.373G>A (p.Gly125Arg) in CDKN2A (p14ARF) transcript. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 16374456). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp110*) 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). 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. |
| Color Diagnostics, |
RCV002323583 | SCV004361303 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-16 | criteria provided, single submitter | clinical testing | The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant changes 1 nucleotide in exon 2 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 missing the C-terminal sequence that encodes ankyrin repeat 4. This variant has been reported in two individuals affected with melanoma in the literature (PMID: 16374456, 21801156). 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. |
| Database of Curated Mutations |
RCV000432172 | SCV000505628 | likely pathogenic | Neoplasm | 2015-07-14 | no assertion criteria provided | literature only | |
| Institute of Medical Sciences, |
RCV001255669 | SCV001432234 | pathogenic | Lip and oral cavity carcinoma | 2019-04-30 | no assertion criteria provided | research |