Submissions for variant NM_000077.5(CDKN2A):c.301G>T (p.Gly101Trp)

dbSNP: rs104894094

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212400	SCV000149243	pathogenic	not provided	2024-05-28	criteria provided, single submitter	clinical testing	Reported in association with familial melanoma and pancreatic cancer, and is a common pathogenic founder variant observed to segregate with disease in numerous geographically-diverse families (PMID: 7987387, 7666917, 10869234, 11807902, 14679123, 19500876, 26775776, 26681309); Published functional studies demonstrate a damaging effect: impaired cell cycle inhibition and CDK4 and CDK6 binding (PMID: 7647780, 7780957, 8668202, 9324288, 19260062, 20340136, 21462282, 24659262); This variant in the p16 isoform also results in a variant of uncertain significance in the p14-ARF protein, c.344G>T (p.Arg115Leu); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22804906, 19158841, 26225579, 27181379, 25787093, 22841127, 26650572, 25970827, 36980738, 35988656, 36717525, 32191290, 36495689, 28146043, 28452926, 28726808, 7780957, 7777061, 8668202, 9324288, 10389768, 19260062, 20340136, 21462282, 18024887, 10869234, 17167857, 25780468, 15235029, 15140239, 10874641, 25803691, 7987388, 19500876, 7566978, 14679123, 7647780, 24659262, 7987387, 19360740, 15860862, 11807902, 26681309, 22368299, 25023876, 25431349, 26775776, 26800492, 26892652, 26650189, 27473757, 26658419, 28060055, 26381259, 28030792, 28592523, 27926368, 29464027, 20653773, 7666917, 29543703, 30113427, 30338612, 31432501, 11243640, 36139606, 12001124, 27960642, 21801156, 8012957, 16818274, 27756164, 9166859, 9425228, 15146471, 11579459, 8552158, 7718873, 29922827, 32482799, 18519632, 35123577, 31628766, 30218143, 30291219, 28765326)
Ambry Genetics	RCV000115334	SCV000184621	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	The p.G101W pathogenic mutation (also known as c.301G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 301. The glycine at codon 101 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in numerous individuals diagnosed with FAMMM (Whelan AJ et al. N. Engl. J. Med. 1995 Oct;333:975-7; Ranade K et al. Nat. Genet.,1995 May;10:114-6; Gironi LC et al. Int. J. Dermatol. 2015 Dec;54:e553-5; Roberts NJ et al. Cancer Discov. 2016 Feb;6:166-75). It has also been reported as one of the most common CDKN2A mutations (Vinarsky V et al. Head Neck. 2009;31:1524-7; Puig S et al. Genet Med, 2016 07;18:727-36). In one meta-analysis, 9 of 22 families with this mutation reported at least one case of pancreatic cancer (Goldstein AM et al. Hum. Mutat. 2004; 23:630). Several functional studies have revealed a significant decrease in the ability of p.G101W to inhibit cell growth (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Miller PJ et al. Hum. Mutat. 2011;32:900-11). In addition, while some studies have shown that the mutant protein maintains some ability to bind with CDK4, additional studies have demonstrated that the binding affinity is temperature dependent, with 75% of binding affinity compared to wildtype at 30 degrees Celsius, but <10% of binding affinity compared to wildtype at 42 degrees Celsius (Walker GJ et al. Int. J. Cancer. 1999;82:305-12; Kannengiesser C et al. Hum. Mutat. 2009;30:564-74; Parry D et al. Mol. Cell. Biol. 1996 Jul;16(7):3844-52). Further, mass spectrometry analysis of this alteration indicates a significantly altered structure, and in silico molecular dynamics simulations predict that this alteration creates a misfolding of the third and fourth ankryin repeats, with a partial conservation of the first and second repeats at the binding site, which explains its partial retention of CDK4 binding in vitro but its inability to block cell proliferation (Tevelev A et al. Biochemistry. 1996 Jul;35(29):9475-87; Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). The partially folded state is predicted to promote faster degradation, resulting in a decreased half-life of the protein and a higher tendency to form protein aggregates (Scaini MC et al. Hum. Mutat. 2014 Jul;35(7):828-40). Of note, this pathogenic mutation has also been reported in the literature as p.G93W (c.295G>T). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196633	SCV000253762	pathogenic	Familial melanoma	2024-01-29	criteria provided, single submitter	clinical testing	The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 101 of the CDKN2A (p16INK4a) protein (p.Gly101Trp). 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: 10869234, 11807902, 14679123, 15146471, 21462282, 21801156). It has also been observed to segregate with disease in related individuals. This variant is also known as c.344G>T (p.Arg115Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9412). 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. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 20340136, 21462282). For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415140	SCV000492851	pathogenic	Melanoma	2015-06-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212400	SCV000601024	pathogenic	not provided	2017-07-17	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. Statistically associated with disease in multiple families.
Counsyl	RCV000010019	SCV000677725	pathogenic	Melanoma-pancreatic cancer syndrome	2017-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115334	SCV000684520	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-27	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 glycine with tryptophan at codon 101 in the ankyrin repeat motif of the CDKN2A (p16INK4A) protein. This variant is also known as p.Gly93Trp in the literature. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant impairs the ability of p16INK4A protein to bind CDK4 and CDK6 and control cell cycle (PMID: 7566978, 7647780, 9324288, 19260062, 20340136, 21462282, 24659262). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 9425228, 11579459, 12072543, 14679123, 15146471, 15860862, 16234564, 19360740, 20340136, 21801156, 22841127, 25780468, 26381259, 26658419, 26681309, 26775776, 27181379, 28146043, 29464027, 29945567, 30274933, 31432501, 31517177, 32455486). This variant has been shown to segregate with disease in many families (PMID: 7666917, 7987387, 8552158, 9425228, 10508477) and is thought to be a European founder mutation (PMID: 10869234, 11579459, 15860862). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000212400	SCV000705284	pathogenic	not provided	2017-01-17	criteria provided, single submitter	clinical testing
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
CeGaT Center for Human Genetics Tuebingen	RCV000212400	SCV001246066	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	CDKN2A: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting, BP4
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000010019	SCV001499646	pathogenic	Melanoma-pancreatic cancer syndrome	2020-04-02	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212400	SCV001762158	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000010018	SCV002518658	pathogenic	Melanoma, cutaneous malignant, susceptibility to, 2	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000196633	SCV002547810	pathogenic	Familial melanoma	2022-05-12	criteria provided, single submitter	clinical testing	Variant summary: CDKN2A c.301G>T (p.Gly101Trp) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 234668 control chromosomes (gnomAD, Kamb_1994). c.301G>T has been reported in the literature in multiple individuals affected with Melanoma (e.g. Kamb_1994, Hussussian_1994, Blackwood_2002). These data indicate that the variant is very likely to be associated with disease. . Kannengiesser_2008 reports that the variant causes a loss of CDK4 binding which results in aberrant proliferation in cell culture. This was was confirmed by Miller_2011, who showed that in a cell cycle arrest assay, the variant caused a complete loss of cell cycle arrest. Twelve ClinVar submitters have assessed the variant since 2014: all have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212400	SCV002550362	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000010018	SCV002579411	pathogenic	Melanoma, cutaneous malignant, susceptibility to, 2	2021-08-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000010019	SCV004018548	pathogenic	Melanoma-pancreatic cancer syndrome	2023-04-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11556834, 17047042].
Baylor Genetics	RCV003473075	SCV004212514	pathogenic	Melanoma and neural system tumor syndrome	2024-02-28	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000212400	SCV005196963	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000010018	SCV000030239	risk factor	Melanoma, cutaneous malignant, susceptibility to, 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