9-21974761-C-T

Variant names:

• chr9-21974761-C-T
• rs1131691186
• NM_000077.5:c.67G>A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.67G>A​(p.Gly23Ser) 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 pathogenic 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. G23R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.55

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 16 ACMG points.

• PM1: In a repeat ANK 1 (size 29) in uniprot entity CDN2A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr9-21974761-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886
• PP5: Variant 9-21974761-C-T is Pathogenic according to our data. Variant chr9-21974761-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.67G>A	p.Gly23Ser	missense_variant	Exon 1 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3553G>A		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.67G>A	p.Gly23Ser	missense_variant	Exon 1 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-3553G>A		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma and neural system tumor syndrome Pathogenic:1

Jun 10, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Dec 06, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in multiple families with melanoma, and suggested to be a founder variant in Central Italy (Begg et al., 2005; Gensini et al., 2007; Taylor et al., 2017; Casula et al., 2019); 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); Published functional studies are inconclusive: variant demonstrated an intermediate effect in an in vitro proliferation assay (Scaini et al., 2014); This variant is associated with the following publications: (PMID: 16234564, 28830827, 31382929, 28440912, 17218939, 28508593, 17992122, 33237286, 24659262) -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 23, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G23S variant (also known as c.67G>A), located in coding exon 1 of the CDKN2A gene, results from a G to A substitution at nucleotide position 67. The glycine at codon 23 is replaced by serine, an amino acid with similar properties. This alteration has been seen in multiple individuals and families with melanoma and has been reported as an Italian founder mutation based on location in a functionally important domain of the protein, strong segregation analyses and haplotype analyses showing one common ancestral origin (Begg CB et al. J. Natl. Cancer Inst. 2005 Oct;97(20):1507-15; Gensini F et al. Melanoma Res. 2007 Dec;17(6):387-92; Bruno W. J Am Acad Dermatol . 2016 Feb;74(2):325-32;Taylor NJ et al. J. Invest. Dermatol., 2017 12;137:2606-2612; Casula M et al. BMC Cancer, 2019 Aug;19:772; Ambry internal data). In addition, structural analysis predicts that the p.G23S variant results in severe perturbation of the protein, likely resulting in misfolding and loss of binding (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma Pathogenic:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 23 of the CDKN2A (p16INK4a) protein (p.Gly23Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cutaneous melanoma (PMID: 16234564, 16896043, 17992122, 21462282, 26223839, 28830827, 31382929). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 429108). 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: 24659262). This variant disrupts the p.Gly23 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9856841, 16234564, 17167857, 24659262, 26775776, 27267843, 28830827, 29661971; internal data). 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, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.43	D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.68
MutPred		0.43		Gain of glycosylation at G23 (P = 0.0174);Gain of glycosylation at G23 (P = 0.0174);Gain of glycosylation at G23 (P = 0.0174);
MVP		0.92
MPC		1.2
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.58
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1131691186; hg19: chr9-21974760; COSMIC: COSV58709325; COSMIC: COSV58709325;