NM_000077.5:c.340_355delCCCGTGGACCTGGCTG

Variant names:

• chr9-21971003-TCAGCCAGGTCCACGGG-T
• rs1554653956
• NM_000077.5:c.340_355delCCCGTGGACCTGGCTG

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.340_355delCCCGTGGACCTGGCTG​(p.Pro114ArgfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P114P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-21971003-TCAGCCAGGTCCACGGG-T is Pathogenic according to our data. Variant chr9-21971003-TCAGCCAGGTCCACGGG-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 463500.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.340_355delCCCGTGGACCTGGCTG	p.Pro114ArgfsTer27	frameshift_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.383_398delCCCGTGGACCTGGCTG	p.Ala128GlufsTer39	frameshift_variant, stop_lost	Exon 2 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.340_355delCCCGTGGACCTGGCTG	p.Pro114ArgfsTer27	frameshift_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.383_398delCCCGTGGACCTGGCTG	p.Ala128GlufsTer39	frameshift_variant, stop_lost	Exon 2 of 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

Jul 27, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 31, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial melanoma Pathogenic:1

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554653956; hg19: chr9-21971002;