ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.159G>C (p.Met53Ile) (rs104894095)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160421 SCV000212879 pathogenic Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification
GeneDx RCV000212399 SCV000210954 pathogenic not provided 2018-04-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted CDKN2A c.159G>C at the cDNA level, p.Met53Ile (M53I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATC). This variant has been observed in over 20 individuals of various ethnicities with a personal and/or family history of melanoma, segregated with cancer in multiple families, and has been identified as a founder variant in the Scottish population (Walker 1995, MacKie 1998, Tsao 2000, Box 2001, Goldstein 2004, Lang 2005, Kannengiesser 2007, Lang 2007, Helsing 2008, Harland 2014). Several in vitro studies demonstrated the pathogenic effect of this variant, in particular finding significantly reduced binding to CDK4 compared to wild-type (Sun 1997, Monzon 1998, Becker 2001, McKenzie 2010). CDKN2A Met53Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the second ANK repeat (UniProt) . In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000205342 SCV000260919 pathogenic Hereditary cutaneous melanoma 2018-12-26 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 methionine with isoleucine at codon 53 of the CDKN2A (p16INK4a) protein (p.Met53Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. Alternatively, this sequence change replaces aspartic acid with histidine at codon 68 of the CDKN2A (p14ARF) protein (p.Asp68His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is present in population databases (rs104894095, ExAC 0.02%). This variant has been reported to segregate with disease in affected individuals from many melanoma families (PMID: 16905682, 8595405, 9699728, 16307646, 9328469, 17171691). It has been identified predominantly in melanoma patients with Scottish ancestry. Haplotype analysis suggests that this may be a common founder mutation (PMID: 17171691). ClinVar contains an entry for this variant (Variation ID: 9414). Functional studies including yeast 2-hybrid and in vitro binding assays demonstrate that the p.Met53Ile in p16INK4a results in significantly decreased binding to CDK4 compared to the wild-type protein (PMID: 9389568, 11595726, 9328469). In addition, functional studies in melanoma cells with a p53-proficient/ARF-deficient background demonstrated that p.Asp68His in p14ARF resulted in diminished senescence and superoxide production, as well as reduced interaction between BCL-xL and p14ARF (PMID: 25370744). For these reasons, this variant has been classified as Pathogenic. The evidence indicates that this variant confers risk of developing both CDKN2A p16INK4a-associated and p14ARF-associated conditions.
OMIM RCV000010021 SCV000030242 risk factor Cutaneous malignant melanoma 2 1998-08-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212399 SCV000601018 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing

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