9-21971100-G-C

Variant names:

• chr9-21971100-G-C
• rs749714198
• NM_000077.5:c.259C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 7P and 1B. PM1 PM2 PM5 PP5 BP4

The NM_000077.5(CDKN2A):​c.259C>G​(p.Arg87Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. R87L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.952
• Publications: 25 publications found

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

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP5: Variant 9-21971100-G-C is Pathogenic according to our data. Variant chr9-21971100-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2735264.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4164617). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.259C>G	p.Arg87Gly	missense	Exon 2 of 3	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.302C>G	p.Pro101Arg	missense	Exon 2 of 3	NP_478102.2
	CDKN2A	NM_001195132.2		c.259C>G	p.Arg87Gly	missense	Exon 2 of 4	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.259C>G	p.Arg87Gly	missense	Exon 2 of 3	ENSP00000307101.5
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.302C>G	p.Pro101Arg	missense	Exon 2 of 3	ENSP00000462950.1
	CDKN2A	ENST00000498124.1	TSL:1	c.259C>G	p.Arg87Gly	missense	Exon 2 of 4	ENSP00000418915.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial melanoma Pathogenic:1

Apr 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 7987387, 8668202, 10491434, 12352668, 21462282). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 87 of the CDKN2A (p16INK4a) protein (p.Arg87Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial cutaneous melanoma (PMID: 11815963). It has also been observed to segregate with disease in related individuals. This variant is also known as a missense mutation of codon 87, which changes GGG to CGG in CDKN2A (p16INK4a) transcript and as c.302C>G (p.Pro101Arg) in CDKN2A (p14ARF) transcript. 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. 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. 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.

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R87G variant (also known as c.259C>G), located in coding exon 2 of the CDKN2A gene, results from a C to G substitution at nucleotide position 259. The arginine at codon 87 is replaced by glycine, an amino acid with dissimilar properties. Of note, this variant is also known as p.P101R (c.302C>G) in the p14(ARF) isoform. This variant was identified in individuals with features consistent with melanoma-pancreatic cancer syndrome and segregated with disease in at least one family (Lynch HT et al. Cancer, 2002 Jan;94:84-96; Middlebrooks CD et al. Cancer Res, 2019 Jun;79:2992-3000). Other variant(s) at the same codon, p.R87W (c.259C>T), have been identified in individual(s) 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). 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 available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	-0.075	T
PhyloP100		0.95
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.44
Sift	Benign	0.032	D
Sift4G	Uncertain	0.054	T
Vest4		0.44
MVP		0.99
ClinPred		0.92	D
GERP RS		5.0
PromoterAI		0.031	Neutral
Varity_R		0.69
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs749714198; hg19: chr9-21971099;