rs1554656411

Positions:

• chr9-21974749-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.79G>T​(p.Glu27Ter) variant causes a stop gained 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E27E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -0.130

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 139 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21974749-C-A is Pathogenic according to our data. Variant chr9-21974749-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 463512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21974749-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.79G>T	p.Glu27Ter	stop_gained	1/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.194-3541G>T		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.79G>T	p.Glu27Ter	stop_gained	1/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.194-3541G>T		intron_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: 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	Ambry Genetics	Nov 25, 2019	The p.E27* variant (also known as c.79G>T), located in coding exon 1 of the CDKN2A gene, results from a G to T substitution at nucleotide position 79. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This variant has been reported in familial melanoma kindreds and in apparently sporadic melanoma cases and is an Italian founder mutation (Ghiorzo P et al. Hum. Mol. Genet. 2006 Sep;15:2682-9). It has also been reported in patients with pancreatic cancer, including those from families with multiple cases of pancreatic cancer (Ghiorzo P et al. J. Med. Genet. 2012 Mar;49:164-70). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 01, 2023	This variant changes 1 nucleotide in exon 1 of the CDKN2A (p16INK4A) gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. The variant has been shown to significantly reduce p16 protein levels (PMID: 16893909). This variant has been reported in numerous individuals affected with melanoma and pancreatic cancer (PMID: 16893909, 17047042, 18024887, 18023021, 22368299, 27804060, 35777164), and has been shown to segregate with disease in melanoma kindreds (PMID: 16893909). Haplotype analysis has indicated that this variant is an Italian founder mutation (PMID: 16893909). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 11, 2023

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2015

This pathogenic variant is denoted CDKN2A c.79G>T at the cDNA level and p.Glu27Ter (E27X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamic Acid to a premature stop codon (GAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with melanoma and pancreatic cancer and was shown to result in significantly decreased p16 protein levels (Ghiorzo 2006, Ghiorzo 2012). We therefore consider this variant to be pathogenic. -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 02, 2023

ClinVar contains an entry for this variant (Variation ID: 463512). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with two primary melanomas and melanoma (PMID: 16893909, 17047042, 18023021, 27804060). It is commonly reported in individuals of Italian ancestry (PMID: 16893909, 17047042, 18023021, 27804060). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu27*) in the CDKN2A (p16INK4a) gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.26
Eigen_PC	Benign	-0.0069
FATHMM_MKL	Benign	0.50	D
MutationTaster	Benign	1.0	A;A;A;A;D;D;D;D;D
Vest4		0.57
GERP RS		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1554656411; hg19: chr9-21974748; COSMIC: COSV58688166; COSMIC: COSV58688166;