ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.212A>G (p.Asn71Ser) (rs559848002)

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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 RCV000571231 SCV000673234 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Color RCV000571231 SCV000903513 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000478806 SCV000564857 likely pathogenic not provided 2014-10-13 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.212A>G at the cDNA level, p.Asn71Ser (N71S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant was observed in multiple families with personal and family histories consistent with familial atypical multiple mole melanoma (FAMMM) syndrome (Della Torre 2001, Bishop 2002, Mantelli 2002, Goldstein 2007). CDKN2A Asn71Ser was found to bind CDK4 and CDK6 similarly to wild type by co-immunoprecipitation assay (Walker 1999, Yarbrough 1999). However, a two-hybrid assay indicated reduced binding to both CDK4 and CDK6 (McKenzie 2010). Yarbrough (1999) also found that CDKN2A exhibited intact inhibition of CDK6 and CDK-activating complex activities by in vitro kinase inhibition assay. However; CDKN2A Asn71Ser showed reduced ability to inhibit cell growth and to induce cell-cycle arrest (Walker 1999, Yarbrough 1999). A Bayesian analysis using functional, segregation and in silico data predicted CDKN2A Asn71Ser to be pathogenic (Miller 2011). CDKN2A Asn71Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. CDKN2A Asn71Ser occurs at a position that is highly conserved in mammals and is located in AK2 repeat (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider CDKN2A Asn71Ser to be a likely pathogenic variant.
Invitae RCV000692301 SCV000820115 likely pathogenic Hereditary cutaneous melanoma 2018-04-02 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 71 of the CDKN2A (p16INK4a) protein (p.Asn71Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs559848002, ExAC 0.01%). This variant has been reported in several individuals and families affected with melanoma (PMID: 7987387, 21462282, 10861313, 12072543, 11556834, 18363633, 22841127, 10390011). This variant is also known as p.Asn63Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 418121). Experimental studies have shown that this missense change impairs the CDKN2A (p16INK4a) protein function in regulating cell cycle arrest and cell proliferation (PMID: 21462282, 10491434, 7566978, 7647780, 10389768, 10498896). Conflicting data in several functional studies have shown that the CDK4 or CDK6 binding affinity of this variant is either significantly lower than wild type (PMID: 20340136, 7566978, 19260062), or at comparable level of the wild type protein (PMID: 21462282, 10491434, 10389768, 10498896). In one of these studies, it has been suggested that normal binding to CDK4 or CDK6 is a poor predictor of cell cycle function and pathogenicity (PMID: 21462282). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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