rs1060501263

Positions:

• chr9-21971000-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.358del​(p.Glu120SerfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E120E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.05

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971000-TC-T is Pathogenic according to our data. Variant chr9-21971000-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 406710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971000-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.358del	p.Glu120SerfsTer26	frameshift_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.*2del		3_prime_UTR_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.358del	p.Glu120SerfsTer26	frameshift_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*2del		3_prime_UTR_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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	Jan 15, 2020	This variant deletes 1 nucleotide in exon 2 of the CDKN2A gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 20, 2023	The c.358delG pathogenic mutation, located in coding exon 2 of the CDKN2A gene, results from a deletion of one nucleotide at nucleotide position 358, causing a translational frameshift with a predicted alternate stop codon (p.E120Sfs*26). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of CDKN2A, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 37 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time. However, this alteration has been identified in multiple Spanish patients and families with cutaneous malignant melanoma and was shown to segregate with disease in four individuals in a family (Puig S et al. Hum. Genet., 1997 Dec;101:359-64; De Unamuno B et al. Melanoma Res., 2018 06;28:246-249; de Torre C et al. Exp. Dermatol., 2010 Aug;19:e333-5). In addition, this variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 14, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val126 amino acid residue in CDKN2A (p16INK4a). Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7647780, 7987387, 8668202, 10389768, 11595726, 23371019). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 406710). This premature translational stop signal has been observed in individual(s) with melanoma and other cancer types (PMID: 539244, 9439668, 10874641, 25780468, 26681309). 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 creates a premature translational stop signal (p.Glu120Serfs*26) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the CDKN2A (p16INK4a) protein. -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1060501263; hg19: chr9-21970999;