rs730881674

Variant names:

• chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C
• rs730881674
• NM_000077.5:c.225_243delCGCCACTCTCACCCGACCC

Your query was ambiguous. Multiple possible variants found:

• chr9-21971115-CGGGTCGGGTGAGAGTGGCG-C
• chr9-21971115-CGGGTCGGGTGAGAGTGGCG-CGGGTCGGGTGAGAGTGGCGGGGTCGGGTGAGAGTGGCG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.225_243delCGCCACTCTCACCCGACCC​(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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P75P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• 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]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 [Likely_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 rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.225_243delCGCCACTCTCACCCGACCC	p.Ala76CysfsTer64	frameshift_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.268_286delCGCCACTCTCACCCGACCC	p.Arg90ValfsTer76	frameshift_variant	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.225_243delCGCCACTCTCACCCGACCC	p.Ala76CysfsTer64	frameshift_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.268_286delCGCCACTCTCACCCGACCC	p.Arg90ValfsTer76	frameshift_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

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 AC: 0 AN: 33438

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44656

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26070

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39670

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86164

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 44694

Gnomad4 NFE exome AF: 9.00e-7 AC: 1 AN: 1111496

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Melanoma-pancreatic cancer syndrome Pathogenic:2

Apr 27, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 04, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 07, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 21, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDKN2A-related disorder Pathogenic:1

Apr 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 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

Feb 21, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Familial pancreatic carcinoma Pathogenic:1

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial melanoma Pathogenic:1

Sep 04, 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.Ala76Cysfs*64) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 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, cutaneous malignant melanoma, and familial atypical multiple mole melanoma (PMID: 7640518, 16905682, 17047042, 20340136, 22636603, 23897584, 109563903). It is commonly reported in individuals of Dutch ancestry (PMID: 7640518, 16905682, 17047042, 20340136, 22636603, 23897584, 109563903). This variant is also known as the p16-Leiden variant and c.268_286del (p.Arg90Valfs*76) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 182411). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CDKN2A (p16INK4a) function (PMID: 20340136). 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

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

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; COSMIC: COSV58696968; COSMIC: COSV58696968;