rs763804037

Positions:

• chr9-21974685-G-A
• chr9-21974685-G-C
• chr9-21974685-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.143C>T​(p.Pro48Leu) variant causes a missense change. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P48T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 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 turn (size 2) in uniprot entity CDN2A_HUMAN there are 4 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 chr9-21974686-G-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 9-21974685-G-A is Pathogenic according to our data. Variant chr9-21974685-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2625888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.143C>T	p.Pro48Leu	missense_variant	1/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-3477C>T		intron_variant		ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.143C>T	p.Pro48Leu	missense_variant	1/3	1	NM_000077.5	ENSP00000307101	P2
CDKN2A	ENST00000579755.2	c.194-3477C>T		intron_variant		1	NM_058195.4	ENSP00000462950

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2023

The p.P48L variant (also known as c.143C>T), located in coding exon 1 of the CDKN2A gene, results from a C to T substitution at nucleotide position 143. The proline at codon 48 is replaced by leucine, an amino acid with similar properties. This variant has been reported in multiple hereditary melanoma families, and was shown to segregate with disease in at least one family (Platz A et al. J Natl Cancer Inst, 1997 May;89:697-702; Helgadottir H et al. J Natl Cancer Inst, 2016 Nov;108; Taylor NJ et al. J Invest Dermatol, 2017 Dec;137:2606-2612). The p.P48L variant consistently demonstrated reduced binding or impaired CDK4/6 kinase activity, and a loss of the ability to induce cell cycle arrest across multiple functional studies (Hashemi J et al. Melanoma Res, 1999 Feb;9:21-30; Yarbrough WG et al. J Natl Cancer Inst, 1999 Sep;91:1569-74; Ruas M et al. Oncogene, 1999 Sep;18:5423-34). Another alteration at the same codon, p.P48T (c.142C>A), has been described in multiple individuals with histories of cutaneous melanoma and/or pancreatic cancer (Moore PS et al. Hum Mutat, 2000 Nov;16:447-8; Foppiani L et al. Eur J Endocrinol, 2008 Mar;158:417-22; Menin C et al. Pigment Cell Melanoma Res, 2011 Aug;24:728-30; Bruno W et al. J Am Acad Dermatol, 2016 Feb;74:325-32; de Ávila AL et al. Fam Cancer, 2014 Dec;13:645-9; Puig S et al. Genet Med, 2016 07;18:727-36). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well 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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro48 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11556834, 21462282). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 10491434). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with Familial cutaneous melanoma (PMID: 9168184, 10338331, 21462282). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 48 of the CDKN2A (p16INK4a) protein (p.Pro48Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Pathogenic	0.77
Sift	Benign	0.030	D;.;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.76
MutPred		0.82		Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);Loss of disorder (P = 0.036);
MVP		1.0
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.48
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-21974684; COSMIC: COSV58683273; COSMIC: COSV58683273;