9-21971109-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000077.5(CDKN2A):c.250G>A(p.Asp84Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D84Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:2

Conservation

PhyloP100: 7.31

Publications

88 publications found

Variant links:

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]

CDKN2A Gene-Disease associations (from GenCC):

melanoma, cutaneous malignant, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
melanoma-pancreatic cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atypical multiple mole melanoma syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma and neural system tumor syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CDKN2A links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 46 uncertain in NM_000077.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-21971109-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376306.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 9-21971109-C-T is Pathogenic according to our data. Variant chr9-21971109-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 229806.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.250G>A	p.Asp84Asn	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.293G>A	p.Arg98Gln	missense_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 link	c.250G>A	p.Asp84Asn	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 link	c.293G>A	p.Arg98Gln	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

231524

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1452146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722814

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26072

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44888

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5452

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111540

Other (OTH)

AF:

0.00

AC:

AN:

60254

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Melanoma-pancreatic cancer syndrome

Pathogenic:2Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Uncertain significance and reported on 01-05-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Sep 15, 2021

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces aspartic acid with asparagine at codon 84 in the ankyrin repeats of the CDKN2A protein. Computational prediction tool 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). Functional studies have shown that this variant results in the loss of ability to bind CDK4 and CDK6 proteins (PMID: 10498896, 21462282, 29091774, 34099663) and control cell cycle (PMID: 21462282). This variant has been reported in multiple individuals affected with multiple primary melanomas or familial melanoma (PMID: 18803811, 21462282, 22841127, 33945383) and has been observed in tumor samples from 19 individuals with advanced melanoma (PMID: 31980996). 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 Likely Pathogenic. -

Aug 06, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D84N variant (also known as c.250G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 250. The aspartic acid at codon 84 is replaced by asparagine, an amino acid with highly similar properties. This alteration was detected in a Slovenian patient with multiple primary cutaneous melanomas (CM) who has no family history and in a French patient with a CM who has a first-degree relative with a CM (Peric B, BMC Med. Genet. 2008 ; 9():86; Maubec E, J. Am. Acad. Dermatol. 2012 Dec; 67(6):1257-64). An in vitro protein functional assay showed that expressed protein with this alteration was unable to bind to CDK4 or CDK6 (Ruas M, Oncogene 1999 Sep; 18(39):5423-34). Another functional study showed this alteration had a reduced functional capacity compared to wild-type in a cell cycle analysis assay, but the effect was determined to be indeterminate (Koh J et al. Nature 1995 Jun;375(6531):506-10.) Based on internal structural analysis, D84N is more disruptive to the CDKN2A-CDK protein interaction interface than a nearby pathogenic variant (Ambry internal data; Yuan, C. Protein Sci 2000 Jun;9(6):1120-8; Russo A et al. Nature 1998 Sep;395(6699):237-43). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma

Uncertain:1

May 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 84 of the CDKN2A (p16INK4a) protein (p.Asp84Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 18803811, 21462282, 22841127, 33945383). This variant is also known as c.293G>A (p.Arg98Gln) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 229806). 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: 10498896, 21462282). This variant disrupts the p.Asp84 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10491434, 21462282, 28060055). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:-

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.52

D;T;.;.;.;.;T;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D;.;D;.;D;D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.30

PhyloP100

7.3

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.7

D;.;.;D;.;.;.;.

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0010

D;.;.;D;.;.;.;.

Sift4G

Uncertain

0.022

D;T;D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.;.;.

Vest4

0.76

MutPred

0.40

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);.;Loss of loop (P = 0.1242);.;.;.;.;

MVP

0.97

MPC

1.2

ClinPred

0.98

GERP RS

5.9

PromoterAI

-0.0027

Neutral

(source)

Varity_R

0.74

gMVP

0.85

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over