ClinVar Miner

Submissions for variant NM_000077.4(CDKN2A):c.301G>T (p.Gly101Trp) (rs104894094)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622260 SCV000184621 pathogenic Inborn genetic diseases 2014-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000010019 SCV000897974 pathogenic Melanoma-pancreatic cancer syndrome 2018-04-06 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415140 SCV000492851 pathogenic Cutaneous melanoma 2015-06-18 criteria provided, single submitter clinical testing
Color RCV000115334 SCV000684520 pathogenic Hereditary cancer-predisposing syndrome 2017-04-12 criteria provided, single submitter clinical testing
Counsyl RCV000010019 SCV000677725 pathogenic Melanoma-pancreatic cancer syndrome 2017-02-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000212400 SCV000705284 pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing
GeneDx RCV000212400 SCV000149243 pathogenic not provided 2019-01-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted CDKN2A c.301G>T at the cDNA level, p.Gly101Trp (G101W) at the protein level, and results in the change of a Glycine to a Tryptophan (GGG>TGG). This variant, also reported as Gly93Trp using an alternate transcript, has been reported previously in association with familial melanoma and pancreatic cancer and is the most common founder pathogenic variant seen in numerous geographically-diverse families (Hussussian 1994, Ciotti 2000, Mantelli 2004, Ghiorzo 2007, Bruno 2009, Puig 2015, Bruno 2016). CDKN2A Gly101Trp has also been reported in two probands with squamous cell carcinoma of the head and neck (Whelan 1995, Vinarsky 2009). Multiple functional studies have shown that CDKN2A Gly101Trp impairs the cell cycle inhibition function and binding ability of CDKN2A, with some studies showing a temperature dependent effect in vitro (Koh 1995, Ranade 1995, Yang 1995, Parry 1996, Gombart 1997, Kannengiesser 2009, McKenzie 2010, Miller 2011, Scaini 2014). CDKN2A Gly101Trp was not observed in large population cohorts (Lek 2016). Since Glycine and Tryptophan differ in some properties, this is considered a semi-conservative amino acid substitution. CDKN2A Gly101Trp occurs at a position that is conserved in mammals and is located in the 3rd ANK repeat (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Invitae RCV000196633 SCV000253762 pathogenic Hereditary cutaneous melanoma 2019-01-07 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 glycine with tryptophan at codon 101 of the p16INK4a protein (p.Gly101Trp). The glycine residue is moderately conserved and there is a large physicochemical difference between glycine and tryptophan. Alternatively, this sequence change replaces arginine with leucine at codon 115 of the p14ARF protein (p.Arg115Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals and families affected with melanoma and pancreatic cancer, with strong evidence of segregation with disease (PMID: 10869234, 11807902, 21462282, 21801156, 15146471, 14679123). ClinVar contains an entry for this variant (Variation ID: 9412). Experimental studies have shown that p.Gly101Trp in p16INK4a impairs cell cycle arrest activity (PMID: 20340136). Furthermore, a computational analysis combining multiple variables classified p.Gly101Trp as pathogenic (PMID: 21462282). The functional impact of p.Arg115Leu on p14ARF has not been tested. For these reasons, this variant has been classified as Pathogenic. The evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions and CDKN2A (p14ARF)-associated conditions.
OMIM RCV000010018 SCV000030239 risk factor Cutaneous malignant melanoma 2 2010-06-01 no assertion criteria provided literature only
OMIM RCV000010019 SCV000030240 pathogenic Melanoma-pancreatic cancer syndrome 2010-06-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212400 SCV000601024 pathogenic not provided 2017-07-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506523 SCV000601026 uncertain significance not specified 2017-07-17 criteria provided, single submitter clinical testing

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