Submissions for variant NM_000077.5(CDKN2A):c.212A>G (p.Asn71Ser)

dbSNP: rs559848002

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Ambry Genetics	RCV000571231	SCV000673234	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	The p.N71S variant (also known as c.212A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 212. The asparagine at codon 71 is replaced by serine, an amino acid with highly similar properties. This variant has been reported in familial melanoma families and has been noted to segregate with disease, although unaffected individuals have also been reported to carry the variant (Della Torre G et al. Br. J. Cancer, 2001 Sep;85:836-44; Goldstein AM et al. Cancer Epidemiol. Biomarkers Prev. 2000 Sep; 9(9):889-94, Hussussian CJ et al. Nat. Genet. 1994 Sep; 8(1):15-21). Multiple functional studies have studied the ability of this variant to bind to CDK4 and CDK6 substrates, localize properly in the cell, and perform cell cycle inhibition (Ranade K et al. Nat. Genet. 1995 May; 10(1):114-6, Walker GJ et al. Int. J. Cancer 1999 Jul;82(2):305-12, Yarbrough WG et al. J. Natl. Cancer Inst. 1999 Sep; 91(18):1569-74, McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11). CDK4 and CDK6 binding ability was reportedly at least partially retained in all but one study (Miller et al. 2011), which reported complete loss of CDK4 binding ability. In both Walker et al. and Yarbrough et al., this variant demonstrated abnormal localization of the protein within the cell nucleus. Across all studies, this variant also demonstrated significantly diminished ability to inhibit cell proliferation or perform cell cycle arrest. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000692301	SCV000820115	likely pathogenic	Familial melanoma	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 71 of the CDKN2A (p16INK4a) protein (p.Asn71Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with melanoma (PMID: 7987387, 10390011, 10861313, 11556834, 12072543, 18363633, 21462282, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asn63Ser. ClinVar contains an entry for this variant (Variation ID: 418121). 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 tolerated. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 7566978, 7647780, 10389768, 10491434, 10498896, 19260062, 20340136, 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.
Color Diagnostics, LLC DBA Color Health	RCV000571231	SCV000903513	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-04-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 71 of the CDKN2A (p16INK4A) protein. This variant has been reported in over ten individuals and families affected with melanoma (PMID: 7987387, 21462282, 10861313, 12072543, 11556834, 18363633, 22841127, 10390011). This variant has been identified in 1/211414 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant disrupts the protein function in regulating cell cycle arrest and cell proliferation (PMID: 7566978, 7647780, 10389768, 10491434, 10498896, 21462282). The variant impact on CDKN2A (p16INK4a) binding to CDK4 and CDK6 is inconsistent (PMID: 7566978, 10389768, 10491434, 10498896, 19260062, 20340136, 21462282). However, this binding activity showed a poor correlation with cell cycle control function and clinical relevance (PMID: 21462282). Based on the available evidence, this variant is classified as Likely Pathogenic.
Sema4, Sema4	RCV000571231	SCV002534317	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	curation