rs730881674

chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C

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.225_243del(p.Ala76CysfsTer64) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000689 in 1,451,914 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. P75P) 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:7
• Conservation: PhyloP100: 5.60

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 67 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971115-CGGGTCGGGTGAGAGTGGCG-C is Pathogenic according to our data. Variant chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C is described in ClinVar as [Pathogenic]. Clinvar id is 182411.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.225_243del	p.Ala76CysfsTer64	frameshift_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.268_286del	p.Arg90ValfsTer76	frameshift_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.225_243del	p.Ala76CysfsTer64	frameshift_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.268_286del	p.Arg90ValfsTer76	frameshift_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451914 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 722684

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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

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 19 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2021	The c.225_243del19 pathogenic mutation, located in coding exon 2 of the CDKN2A gene, results from a deletion of 19 nucleotides at nucleotide positions 225 to 243, causing a translational frameshift with a predicted alternate stop codon (p.A76Cfs*64). This mutation has been reported in numerous individuals and families with personal and/or family history consistent with familial atypical multiple mole melanoma (FAMMM) syndrome (Gruis NA et al. Melanoma Res. 1995 Jun;5:169-77; Holland EA et al. Genes Chromosomes Cancer, 1999 Aug;25:339-48; Vasen HF et al. Int. J. Cancer, 2000 Sep;87:809-11; Goldstein AM. Hum. Mutat., 2004 Jun;23:630; Goldstein AM et al. J. Med. Genet., 2007 Feb;44:99-106; Harinck F et al. J. Med. Genet., 2012 Jun;49:362-5). Of note, this alteration is also designated as “p16-Leiden-mutation” in published literature, and has been described as a Dutch founder mutation. Functional analysis of this alteration revealed that transfected cells show altered subcellular localization, and significantly reduced binding affinity to CDK4 relative to wild type cells (McKenzie HA et al. Hum. Mutat. 2010 Jun;31:692-701). The relative risk for pancreatic cancer associated with this specific alteration ranges from 17% (95% CI 3–30) to 47.8% (95% CI 28.4-74.7) (Vasen HF et al. Int. J. Cancer, 2000 Sep;87:809-11; de Snoo FA et al. Clin. Cancer Res. 2008 Nov;14:7151-7). Another study also found that smoking significantly increases risks of various cancers in carriers of this mutation (Potjer TP et al. Eur. J. Hum. Genet. 2015 May;23:711-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 21, 2021

- -

CDKN2A-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2024

The CDKN2A c.225_243del19 variant is predicted to result in a frameshift and premature protein termination (p.Ala76Cysfs*64). It is also known as p16-Leiden, and reported as a Dutch founder variant. This variant has been reported in individuals with melanoma, and cancers of the pancreas and breast (Gruis et al. 1995. PubMed ID: 7640518; Koorstra et al. 2008. PubMed ID: 18813118; Li et al. 2018. PubMed ID: 29316957; Yurgelun et al. 2019. PubMed ID: 29961768). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/182411/). Frameshift variants in CDKN2A are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2022

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: loss of CDK4/CDK6 binding, loss of cell cycle inhibitory activity, and altered subcellular localization (McKenzie 2010); Not observed at significant frequency in large population cohorts (gnomAD); Also known as p16-Leiden and considered a Dutch founder variant; This variant is associated with the following publications: (PMID: 16905682, 29961768, 25227142, 12549483, 23897584, 10956390, 22636603, 9579547, 7640518, 26111702, 27406244, 11815963, 21570156, 12690301, 26670666, 27267843, 27672215, 18813118, 18981015, 15146471, 28592523, 29316957, 29263814, 29769629, 30113427, 31923587, 32953120, 32482799, 31203567, 20340136) -

Melanoma-pancreatic cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Apr 27, 2022

- -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 08, 2020

The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. This sequence change deletes 19 nucleotides from exon 2 of the CDKN2A (p16INK4a) mRNA (c.225_243del), causing a frameshift at codon 76. This creates a premature translational stop signal within the last 15 codons of the penultimate exon of the CDKN2A (p16INK4a) mRNA (p.Ala76Cysfs*64). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acids of the CDKN2A (p16INK4a) protein. Alternatively, this sequence change deletes 19 nucleotides from exon 2 of the CDKN2A (p14ARF) mRNA (c.268_286del), causing a frameshift at codon 90. This extends reading frame beyond the termination signal of the CDKN2A (p14ARF) mRNA (p.Arg90Valfs*76). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acids of the CDKN2A (p14ARF) protein. This particular variant, also known as the p16-Leiden variant in the literature, has been reported in numerous families and individuals affected with pancreatic cancer, cutaneous malignant melanoma, and familial atypical multiple mole melanoma and is considered to be a Dutch founder mutation (PMID: 22636603, 20340136, 23897584, 17047042, 16905682, 109563903, 7640518). ClinVar contains an entry for this variant (Variation ID: 182411). Experimental studies have shown that this variant affects p16INK4a protein localization and reduces p16INK4a binding affinity to CDK4 and CDK6 (PMID: 20340136). Loss-of-function variants in CDKN2A (p16INK4a) are known to be pathogenic (PMID: 15146471, 16905682). For these reasons, this variant has been classified as Pathogenic. -

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: rs730881674; hg19: chr9-21971114;