rs1554653956

Positions:

• chr9-21971003-TCAGCCAGGTCCACGGG-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.340_355delCCCGTGGACCTGGCTG​(p.Pro114fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.18

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 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 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971003-TCAGCCAGGTCCACGGG-T is Pathogenic according to our data. Variant chr9-21971003-TCAGCCAGGTCCACGGG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 463500.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.340_355delCCCGTGGACCTGGCTG	p.Pro114fs	frameshift_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.383_398delCCCGTGGACCTGGCTG	p.Ala128fs	frameshift_variant, stop_lost	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.340_355delCCCGTGGACCTGGCTG	p.Pro114fs	frameshift_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.383_398delCCCGTGGACCTGGCTG	p.Ala128fs	frameshift_variant, stop_lost	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 31, 2022	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This variant deletes 16 nucleotides in exon 2 of the CDKN2A (p16INK4A) gene, creating a frameshift and premature translation stop signal in exon 2. This variant is expected to result in the expression of a truncated protein with the sequence of the C-terminal region, including functionally important ankyrin repeat 4, disrupted (PMID: 8880901). Although functional studies have not been reported, this variant is expected to impair CDKN2A (p16INK4A) protein function. This variant has been reported in an individual affected with exocrine pancreatic cancer (PMID: 29506128). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Other truncation variants impacting ankyrin repeat 4 are known to be pathogenic, which include c.358del (p.Glu120Serfs*26, ClinVar variation ID: 406710) and c.457G>T (p.Asp153Tyr; splice variant causing r.384_457del; p.Tyr129Hisfs*11) (ClinVar variation ID: 216035). Loss of CDKN2A function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2021	The c.340_355del16 variant, located in coding exon 2 of the CDKN2A gene, results from a deletion of 16 nucleotides at nucleotide positions 340 to 355, causing a translational frameshift with a predicted alternate stop codon (p.P114Rfs*27). This alteration occurs at the 3' terminus of theCDKN2A gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 43 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Multiple downstream truncations in CDKN2A have been reported in families with cutaneous malignant melanoma and/or pancreatic cancers (De Unamuno B et al. Melanoma Res, 2018 06;28:246-249; Puig S et al. Hum Genet, 1997 Dec;101:359-64; Ruiz A et al. J Med Genet 1999 Jun;36:490-3; Potrony M et al J Am Acad Dermatol, 2014 Nov;71(5):888-95). This variant has been reported in a cohort of unselected patients with exocrine pancreatic neoplasms (Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074). In addition to the clinical data presented in the literature, 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

Jul 14, 2023

This sequence change creates a premature translational stop signal (p.Pro114Argfs*27) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the CDKN2A (p16INK4a) protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 29506128). This variant is also known as c.383_398del (p.Ala128Glufs*39) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 463500). This variant disrupts a region of the CDKN2A (p16INK4a) protein in which other variant(s) (p.Val126Asp) have been determined to be pathogenic (PMID: 9439668, 20539244, 20653773, 25780468, 26681309). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. While the evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a)-associated conditions, its association with risk for developing CDKN2A (p14ARF)-associated conditions is still unclear. The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554653956; hg19: chr9-21971002;