ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.47T>G (p.Leu16Arg) (rs864622263)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206427 SCV000259897 pathogenic Hereditary melanoma 2020-10-01 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 16 of the CDKN2A (p16INK4a) protein (p.Leu16Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with melanoma and pancreatic cancer (PMID: 15173226, 16169933, 17218939, 21150883). In at least two families, this variant was shown to segregate with disease in many individuals with melanoma or pancreatic cancer (PMID: 15173226, Invitae). ClinVar contains an entry for this variant (Variation ID: 219815). A different missense substitution at this codon (p.Leu16Pro) has been determined to be pathogenic (PMID: 17624602, 21462282, 20340136). This suggests that the leucine residue is critical for CDKN2A (p16INK4a) protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000235523 SCV000292534 pathogenic not provided 2018-08-31 criteria provided, single submitter clinical testing This variant is denoted CDKN2A c.47T>G at the cDNA level, p.Leu16Arg (L16R) at the protein level, and results in the change of a Leucine to an Arginine (CTG>CGG). This variant has been observed in individuals with familial melanoma and/or pancreatic cancer (Goldstein 2004, Orlow 2007, McWilliams 2011, Zhen 2015). Although functional studies have not, to our knowledge, been performed for this variant, a mammalian two-hybrid assay for an amino acid change at the same residue, Leu16Pro, showed that variant to have significantly reduced binding to CDK4 and CDK6 (McKenzie 2010). CDKN2A Leu16Arg was not observed in large population cohorts (Lek 2016). CDKN2A Leu16Arg is located in the ANK1 repeat region (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider CDKN2A Leu16Arg to be pathogenic.
Ambry Genetics RCV000493865 SCV000581505 pathogenic Hereditary cancer-predisposing syndrome 2018-05-30 criteria provided, single submitter clinical testing The p.L16R pathogenic mutation (also known as c.47T>G), located in coding exon 1 of the CDKN2A gene, results from a T to G substitution at nucleotide position 47. The leucine at codon 16 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been observed to segregate with disease in several melanoma families (<span style="background-color:initial">Goldstein AM et al. J. Natl. Cancer Inst. 2000 Jun; 92(12):1006-10; <span style="background-color:initial">Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11<span style="background-color:initial">). Another pathogenic alteration impacting the same codon, p.L16P, has also been observed to segregate with melanoma in several families (<span style="background-color:initial">Soufir N et al. Hum. Mol. Genet. 1998 Feb; 7(2):209-16; <span style="background-color:initial">Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11) and has been <span style="background-color:initial">associated with protein mislocalization and reduced binding to CDK4 and CDK6 (McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Health, Inc RCV000493865 SCV001346826 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing This missense variant replaces leucine with arginine at codon 16 of the CDKN2A (p16INK4A) protein. 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals and families affected with melanoma (PMID: 10861313, 12072543, 15146471, 15173226, 16169933, 16172233, 16234564, 16896043, 17218939, 21150883, 21462282, 25685612) and pancreatic cancer (PMID: 25356972). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at this position, p.Leu16Pro, has been shown to impair p16INK4A protein function and is classified as Pathogenic (PMID: 20340136; ClinVar variation ID: 649266), indicating that leucine at this position is important for p16INK4A protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.

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