ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.167G>T (p.Ser56Ile) (rs104894109)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471463 SCV000545550 pathogenic Hereditary melanoma 2019-10-25 criteria provided, single submitter clinical testing The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change replaces serine with isoleucine at codon 56 of the CDKN2A (p16INK4a) protein (p.Ser56Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine. Alternatively, this sequence change replaces glutamine with histidine at codon 70 of the CDKN2A (p14ARF) protein (p.Gln70His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals and families affected with primary melanoma and cutaneous malignant melanoma, with strong evidence of segregation with disease (PMID: 9425228, 21462282, 9516223, 17492760, 12072543, 15150307, 22841127, 15235029). ClinVar contains an entry for this variant (Variation ID: 9425). Functional in vitro studies have shown that p.Ser56Ile in p16INK4a disrupted the interaction between the p16INK4a and CDK4 proteins and altered its subcellular location in mammalian cells (PMID: 20340136, 9516223). Furthermore, a computational analysis combining multiple variables classified p.Ser56Ile in p16INK4a as pathogenic (PMID: 21462282). In addition, in vitro studies have shown that p.Gln70His in p14ARF results in diminished activity with respect to senescence in melanoma cells (PMID: 25370744). For these reasons, this variant has been classified as Pathogenic. The evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions and CDKN2A (p14ARF)-associated conditions.
Ambry Genetics RCV000573952 SCV000673243 pathogenic Hereditary cancer-predisposing syndrome 2020-02-28 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, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, p.S56I is classified as a pathogenic 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 Cutaneous malignant melanoma 2 2007-08-01 no assertion criteria provided literature only

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