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
Ambry Genetics RCV000573952 SCV000673243 pathogenic Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000471463 SCV000545550 pathogenic Hereditary cutaneous melanoma 2018-11-06 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.
OMIM RCV000010032 SCV000030253 risk factor Cutaneous malignant melanoma 2 2007-08-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759745 SCV000889275 likely pathogenic not provided 2018-03-16 criteria provided, single submitter clinical testing

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