Submissions for variant NM_000077.5(CDKN2A):c.47T>G (p.Leu16Arg)

dbSNP: rs864622263

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206427	SCV000259897	pathogenic	Familial melanoma	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 16 of the CDKN2A (p16INK4a) protein (p.Leu16Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 15173226, 16169933, 17218939, 21150883; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219815). 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 disruptive. This variant disrupts the p.Leu16 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17624602, 20340136, 21462282). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000235523	SCV000292534	pathogenic	not provided	2024-02-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired cell cycle control and abolished interaction with CDK4 and CDK6 (PMID: 33823155); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30039340, 12072543, 9425228, 21150883, 21462282, 17047042, 16234564, 20340136, 15173226, 16896043, 20876876, 10861313, 16905682, 16172233, 25356972, 17218939, 28726808, 29922827, 28830827, 29661971, 34399810, 32482799, 33823155)
Ambry Genetics	RCV000493865	SCV000581505	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-10	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 in multiple individuals with personal and/or family history of melanoma and/or pancreatic cancer (Goldstein AM et al. J. Natl. Cancer Inst. 2000 Jun; 92(12):1006-10; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11; Horn IP et al. J Biol Chem 2021 Apr;296:100634; Overbeek KA et al. J Med Genet, 2021 04;58:264-269; Ambry internal data) and has been shown to segregate with disease in several melanoma families (Goldstein AM et al. J. Natl. Cancer Inst. 2000 Jun; 92(12):1006-10; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11). Another pathogenic alteration impacting the same codon, p.L16P, has also been observed to segregate with melanoma in several families (Soufir N et al. Hum. Mol. Genet. 1998 Feb; 7(2):209-16; Miller PJ et al. Hum. Mutat. 2011 Aug; 32(8):900-11) and has been associated with protein mislocalization and reduced binding to CDK4 and CDK6 (McKenzie HA et al. Hum. Mutat. 2010 Jun; 31(6):692-701). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Color Diagnostics, LLC DBA Color Health	RCV000493865	SCV001346826	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-10	criteria provided, single submitter	clinical testing	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). 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). A functional study has shown that this variant results in reduced protein expression levels, inability to bind CDK4/CDK6, and impairment of the cell cycle control activity (PMID: 33823155). 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 been observed in four multi-generational families affected with malignant melanoma and pancreatic cancer, where this variant has shown segregation with cancers in an autosomal dominant manner (PMID: 33823155). 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 Pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235523	SCV001956876	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000235523	SCV001963493	pathogenic	not provided		no assertion criteria provided	clinical testing