rs749714198

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 12P and 2B. PM1PM5PP5_Very_StrongBP4BS2_Supporting

The NM_000077.5(CDKN2A):c.259C>T(p.Arg87Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000374 in 1,604,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R87G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.952

Publications

25 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: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 45 uncertain in NM_000077.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-21971100-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2735264.

PP5

Variant 9-21971100-G-A is Pathogenic according to our data. Variant chr9-21971100-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 406707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.221715). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.259C>T	p.Arg87Trp	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.302C>T	p.Pro101Leu	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.259C>T	p.Arg87Trp	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 link	c.302C>T	p.Pro101Leu	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000861

AC:

AN:

232208

AF XY:

0.0000156

show subpopulations

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:

0.00000954

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1452390

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722914

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5422

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111550

Other (OTH)

AF:

0.00

AC:

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000638

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jun 21, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 17370310, 21462282, 10874641, 21801156, 27804060, 25780468, 26650572, 25685612, 18023021, 26681309, 30218143, 35001868, Andreev2022[FunctionalStudy], 23190892, Jang2022[CaseReport], 19260062, 15860862, 31567591, 29774366, 33237286) -

Oct 12, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Melanoma-pancreatic cancer syndrome

Pathogenic:2

May 29, 2025

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15860862, 18023021, 19260062, 26650572, 31567591, 21462282]. Functional studies indicate this variant impacts protein function [PMID: 19260062, 23190892]. This variant is expected to disrupt protein structure [Myriad internal data]. -

May 28, 2019

Mendelics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Feb 26, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R87W variant (also known as c.259C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 259. The arginine at codon 87 is replaced by tryptophan, an amino acid with dissimilar properties. Of note, this variant is also known as c.302C>T (p.P101L) in the p14(ARF) isoform. This alteration has been reported in multiple individuals with sporadic melanoma, multiple melanomas, and/or familial melanoma (Ambry internal data; Ruiz A et al. J Med Genet. 1999 Jun;36(6):490-3; Puig S et al. J Clin Oncol. 2005 May 1;23(13):3043-51; Helsing P et al. Genes Chromosomes Cancer. 2008 Feb;47(2):175-84; Cuellar F et al. Br J Dermatol. 2009 Jan;160(1):48-53; Kannengiesser C et al. Hum Mutat. 2009 Apr;30(4):564-74; Nikolaou V et al. Br J Dermatol. 2011 Dec;165(6):1219-22; Di Lorenzo S et al. Cancer Biol Ther. 2016;17(1):83-90; Li C et al. Melanoma Res 2020 06;30(3):247-251). Although a CDK4 binding assay showed only partial loss of CDK4 binding activity, a proliferation assay showed impaired capacity to inhibit proliferation of human diploid fibroblasts (Kannengiesser C et al. Hum Mutat. 2009 Apr;30(4):564-74). Additional functional assays have shown partial activity in a cell cycle arrest assay and impaired capacity to regulate both oxidative stress and cell cycle regulatory activity (Miller PJ et al. Hum Mutat. 2011 Aug;32(8):900-11; Jenkins NC et al. J Invest Dermatol. 2013 Apr;133(4):1043-51). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jun 24, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely 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 arginine with tryptophan at codon 87 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function Functional studies have shown that this variant causes a partial reduction in CDK4 binding (PMID: 19260062) and a significant loss of ability to control cell cycle (PMID: 19260062, 21462282, 23190892). This variant has been reported in at least twenty individuals affected with melanoma (PMID: 10874641, 15860862, 18023021, 19260062, 21462282, 21801156, 26650572) and in an unaffected individual (PMID: 26650572). This variant has been identified in 2/232208 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Melanoma and neural system tumor syndrome

Pathogenic:1

Sep 27, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial melanoma

Pathogenic:1

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 87 of the CDKN2A (p16INK4a) protein (p.Arg87Trp). This variant is present in population databases (rs749714198, gnomAD 0.003%). This missense change has been observed in individual(s) with familial melanoma (PMID: 10874641, 15860862, 18023021, 19260062, 21462282, 26650572, 26681309, 29774366). It has also been observed to segregate with disease in related individuals. This variant is also known as c.302C>T (p.Pro101Leu) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 406707). 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: 19260062, 21462282, 23190892). This variant disrupts the p.Arg87 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7647780, 7987387, 8603820, 12352668). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic. In the absence of additional clinical evidence, this variant has been classified as Likely Pathogenic. While this evidence indicates that the variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, the association of this variant with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

T;T

Eigen

Benign

-0.0072

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.59

.;T

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.50

PhyloP100

0.95

PROVEAN

Uncertain

-3.7

.;D

REVEL

Uncertain

0.47

Sift

Benign

0.033

.;D

Sift4G

Uncertain

0.045

D;D

Vest4

0.22

MVP

0.91

ClinPred

0.69

GERP RS

5.0

PromoterAI

0.0081

Neutral

(source)

Varity_R

0.78

Mutation Taster

=0/100

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over