rs104894094

Variant names:

• chr9-21971058-C-A
• rs104894094
• NM_000077.5:c.301G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-21971058-C-A
• chr9-21971058-C-G
• chr9-21971058-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.301G>T​(p.Gly101Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,605,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:22 O:1
• Conservation: PhyloP100: 0.816

Genes affected

CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

ENSG00000264545 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972
• PP5: Variant 9-21971058-C-A is Pathogenic according to our data. Variant chr9-21971058-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 9412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971058-C-A is described in Lovd as [Pathogenic]. Variant chr9-21971058-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.301G>T	p.Gly101Trp	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.344G>T	p.Arg115Leu	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.301G>T	p.Gly101Trp	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.344G>T	p.Arg115Leu	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1452982 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 723122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74374

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000294 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDKN2A: PP1:Strong, PM1, PM2, PS4:Moderate, PS3:Supporting, BP4 -

Jul 17, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 28, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma-pancreatic cancer syndrome Pathogenic:5

Apr 02, 2020

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 06, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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]. -

Melanoma, cutaneous malignant, susceptibility to, 2 Pathogenic:2 Other:1

Jun 01, 2010

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Jul 10, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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, also known as p.G93W (c.295G>T) in the published literature, 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), segregated with disease in multiple families (Hussussian CJ et al. Nat Genet. 1994 Sep;8(1):15-21; Ambry internal data), and is one of the most common CDKN2A mutations (Vinarsky V et al. Head Neck. 2009;31:1524-7). 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; McKenzie HA et al. Hum Mutat. 2010 Jun;31(6):692-701; 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). In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this alteration is also known as c.344G>T (p.R115L)in the p14(ARF) isoform. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial melanoma Pathogenic:2

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

May 12, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Melanoma and neural system tumor syndrome Pathogenic:1

Feb 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKN2A-related disorder Pathogenic:1

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDKN2A c.301G>T variant is predicted to result in the amino acid substitution p.Gly101Trp. This variant has been reported in several individuals to be causative for melanoma, mesothelioma, and pancreatic cancer (reported as 295 codon 93 Gly to Trp in Hussussian et al. 1994. PubMed ID: 7987387; Betti et al. 2016. PubMed: 27181379; Supplemental table S10, Roberts et al. 2016. PubMed ID: 26658419). In addition, functional studies supports its deleterious effect (Kannengiesser et al. 2009. PubMed ID: 19260062; McKenzie et al. 2010. PubMed ID: 20340136; Miller et al. 2011. PubMed ID: 21462282). This variant has not been reported in a large population database; and, it has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/9412/). In summary, this variant is interpreted as pathogenic. -

Melanoma Pathogenic:1

Jun 18, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Pathogenic:1

Apr 03, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;T;.;.;.;.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.041	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.1	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.77
MutPred		0.83		Gain of MoRF binding (P = 0.0329);Gain of MoRF binding (P = 0.0329);.;Gain of MoRF binding (P = 0.0329);.;.;.;.;
MVP		0.99
MPC		1.3
ClinPred		0.88	D
GERP RS		5.9
Varity_R		0.53
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894094; hg19: chr9-21971057; COSMIC: COSV58692144; COSMIC: COSV58692144;