9-21971099-C-G

Position:

• chr9-21971099-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.260G>C​(p.Arg87Pro) 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.31

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_000077.5 (CDKN2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 9-21971099-C-G is Pathogenic according to our data. Variant chr9-21971099-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 236984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971099-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.260G>C	p.Arg87Pro	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.303G>C	p.Pro101Pro	synonymous_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.260G>C	p.Arg87Pro	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.303G>C	p.Pro101Pro	synonymous_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 11, 2022	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 proline at codon 87 in the ankyrin repeats domain of the CDKN2A (p16INK4A) protein. 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 the mutant protein to exhibit almost complete loss of interaction with CDK4 and CDK6 proteins and cell cycle control function (PMID: 8668202, 10491434, 10498896, 19260062, 21462282). This variant has been reported in at least 6 unrelated individuals affected with familial melanoma (PMID: 7987387, 15146471; Color internal data), with two of these families having relatives affected with pancreatic cancer (PMID: 15146471). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same position, p.Arg87Trp, is known to be disease-causing (ClinVar variation ID: 406707), indicating that arginine at this position is functionally important. Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 2023	The p.R87P pathogenic mutation (also known as c.260G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 260. The arginine at codon 87 is replaced by proline, an amino acid with dissimilar properties. This alteration was identified in multiple individuals diagnosed with CDKN2A-associated disease (Ambry internal data; Yu KK et al. Laryngoscope, 2002 Sep;112:1587-93). This alteration showed loss of function in a cell cycle arrest assay (Miller PJ et al. Hum Mutat, 2011 Aug;32:900-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 13, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 07, 2023

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 87 of the CDKN2A (p16INK4a) protein (p.Arg87Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma, lung cancer, and head and neck squamous cell carcinoma and melanoma (PMID: 7987387, 12352668). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg79Pro in CDKN2a (p16INK4a) transcript, or c.303G>C (Silent) in CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 236984). 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: 8668202, 10491434, 10498896, 19260062, 21462282). 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: 10874641). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;T;.;.;.;.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.35	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.6	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.;.;D;.;.;.;.
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.83
MutPred		0.71		Loss of methylation at R87 (P = 0.0888);Loss of methylation at R87 (P = 0.0888);.;Loss of methylation at R87 (P = 0.0888);.;.;.;.;
MVP		1.0
MPC		1.5
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.95
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878853647; hg19: chr9-21971098; COSMIC: COSV58683633; COSMIC: COSV58683633;