Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000471463 | SCV000545550 | pathogenic | Familial melanoma | 2023-10-17 | criteria provided, single submitter | clinical testing | 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 replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 56 of the CDKN2A (p16INK4a) protein (p.Ser56Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cutaneous malignant melanoma and/or primary melanoma (PMID: 9425228, 9516223, 12072543, 15150307, 15235029, 17492760, 21462282, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as c.210G>T (p.Gln70His) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9425). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 9516223, 20340136, 21462282, 25370744). 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. |
| Ambry Genetics | RCV000573952 | SCV000673243 | pathogenic | Hereditary cancer-predisposing syndrome | 2024-01-29 | criteria provided, single submitter | clinical testing | The p.S56I pathogenic mutation (also known as c.167G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 167. The serine at codon 56 is replaced by isoleucine, an amino acid with dissimilar properties. The p.S56I alteration has been reported in numerous individuals with personal and/or family histories consistent with multiple primary melanoma (Begg CB et al. J. Natl. Cancer Inst., 2005 Oct;97:1507-15; Bishop DT et al. J. Natl. Cancer Inst., 2002 Jun;94:894-903; Chaudru V et al. Cancer Epidemiol. Biomarkers Prev., 2005 Oct;14:2384-90; Kannengiesser C et al. Genes Chromosomes Cancer, 2007 Aug;46:751-60; Landi MT et al. J. Med. Genet., 2004 Jul;41:557-66; Soufir N et al. Hum. Mol. Genet., 1998 Feb;7:209-16; Pellegrini C et al. Melanoma Res., 2017 06;27:258-267). This alteration has also been reported as a suggested founder mutation in individuals of French and Italian background as many patients who carry the p.S56I alteration share a unique haplotype (Kannengiesser C et al. Genes Chromosomes Cancer, 2007 Aug;46:751-60). One functional analysis of this alteration indicated retained ability to bind CDK6 at least as well as the wild-type protein but showed diminished affinity for CDK4 (McKenzie HA et al. Hum. Mutat., 2010 Jun;31:692-701). An additional functional analysis using a cell cycle arrest assay indicated p.S56I results in in vitro function loss (Miller PJ et al. Hum. Mutat., 2011 Aug;32:900-11). Further, this alteration has been shown to bind CDK4 very poorly compared to the wild-type in a yeast based two-hybrid assay (Monzon J et al. N. Engl. J. Med., 1998 Mar;338:879-87). In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000759745 | SCV000889275 | likely pathogenic | not provided | 2018-03-16 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000010032 | SCV000030253 | risk factor | Melanoma, cutaneous malignant, susceptibility to, 2 | 2007-08-01 | no assertion criteria provided | literature only |