rs730881675

chr9-21971105-GCGTCGTGCACGGGT-G

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.240_253del(p.Pro81CysfsTer34) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R80R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.23

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 is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971105-GCGTCGTGCACGGGT-G is Pathogenic according to our data. Variant chr9-21971105-GCGTCGTGCACGGGT-G is described in ClinVar as [Pathogenic]. Clinvar id is 182412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971105-GCGTCGTGCACGGGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.240_253del	p.Pro81CysfsTer34	frameshift_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.283_296del	p.Thr95LeufsTer61	frameshift_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.240_253del	p.Pro81CysfsTer34	frameshift_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.283_296del	p.Thr95LeufsTer61	frameshift_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452314 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 722888

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2013	The CDKN2A c.240_253del mutation has been reported previously in association with familial cutaneous malignant melanoma (Fitzgerald et al., 1996). The deletion causes a frameshift starting with codon Proline 81, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Pro81CysfsX34. This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been observed to be inherited. The variant is found in CDKN2A panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2023	The c.240_253del14 pathogenic mutation, located in coding exon 2 of the CDKN2A gene, results from a deletion of 14 nucleotides at nucleotide positions 240 to 253, causing a translational frameshift with a predicted alternate stop codon (p.P81Cfs*34). This alteration has been described in multiple unrelated individuals with melanoma (FitzGerald MG et al. Proc Natl Acad Sci USA.1996;93(16):8541-5; Niendorf KB et al. J Med Genet. 2006;43:501-506; Goldstein AM et al. J Med Genet. 2007;44(2):99-106; Harland M et al. Hered Cancer Clin Pract 2014;12(1):20). It was also identified in a proband from an atypical malignant melanoma family. In addition to a personal and family history of melanoma, the proband had a history of cutaneous neurofibromas, papillary thyroid cancer, and uterine tumors (Vanneste R et al. Am. J. Med. Genet. A 2013 Jun;161A(6):1425-31). In addition to the clinical data presented in the literature, 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	Jan 15, 2020	This variant deletes 14 nucleotides 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. -

Melanoma-pancreatic cancer syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 20, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Familial melanoma Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2020	Variant summary: CDKN2A c.240_253del14 (p.Pro81CysfsX34) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been found in other databases. The variant was absent in 231476 control chromosomes. c.240_253del14 has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma or other cancers. (FitzGerald_1996, Dudley_2018). These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 16, 2023	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.Pro81Cysfs*34) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 76 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 melanoma or pancreatic cancer (PMID: 7923152, 8710906, 15146471, 15173226, 21150883). It has also been observed to segregate with disease in related individuals. This variant is also known as c.238_251del in the CDKN2A (p16INK4a) transcript, and c.283_296del (p.Thr95Leufs*61) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 182412). This variant disrupts a region of the CDKN2A (p16INK4a) protein in which other variant(s) (p.Val126Asp) have been determined to be pathogenic (PMID: 7647780, 7987387, 8668202, 10389768, 11595726, 20340136, 23190892, 23371019). 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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881675; hg19: chr9-21971104;