rs1800586
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 8P and 1B. PP5_Very_StrongBP4
The ENST00000498124.1(CDKN2A):c.-34G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,509,400 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000066 ( 0 hom. )
Consequence
CDKN2A
ENST00000498124.1 5_prime_UTR
ENST00000498124.1 5_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.827
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PP5
?
Variant 9-21974861-C-A is Pathogenic according to our data. Variant chr9-21974861-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 182414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21974861-C-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.72). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDKN2A | NM_058195.4 | c.194-3653G>T | intron_variant | ENST00000579755.2 | |||
CDKN2A | NM_000077.5 | upstream_gene_variant | ENST00000304494.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDKN2A | ENST00000579755.2 | c.194-3653G>T | intron_variant | 1 | NM_058195.4 | ||||
CDKN2A | ENST00000304494.10 | upstream_gene_variant | 1 | NM_000077.5 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000433 AC: 5AN: 115386Hom.: 0 AF XY: 0.0000474 AC XY: 3AN XY: 63326
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GnomAD4 exome AF: 0.0000656 AC: 89AN: 1357220Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 35AN XY: 668658
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2023 | Describes a nucleotide substitution 34 base pairs upstream of the ATG translational start site of the CDKN2A gene that creates an aberrant ATG translation initiation codon; Published functional studies demonstrate a damaging effect: decreases translation from the wild-type ATG and results in a truncated protein that significantly affects reporter activity (Liu et al., 1999; Bisio et al., 2010); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 26557774, 26775776, 19523171, 16896043, 25780468, 9916806, 20093296, 26581427, 26681309, 26099287, 12072543, 26681312, 16397522, 16905682, 15146471, 28495237, 29263814, 28830827, 30067863, 30117292, 30113427, 31567591, 33077847, 32482799, 34598035, 17713569, 29922827) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | CDKN2A: PP1:Strong, PM2, PS3:Moderate, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 05, 2019 | The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one patient with expected phenotype for this gene. Low nucleotide conservation. Assessment of experimental evidence suggests this variant results in abnormal protein function. Very strong co-segregation with disease, and data include affected and unaffected individuals from multiple families. - |
Melanoma-pancreatic cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 03, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 29, 2022 | The c.-34G>T pathogenic mutation is located in the 5' untranslated region (5'UTR) of the CDKN2A gene. This mutation results from a G to T substitution 34 nucleotides upstream from the first translated codon. This sequence alteration creates a potential AUG initiation codon at base -35 and translation initiation from this novel start site predicts a truncated protein with no homology to wild type (Liu L et al. Nat. Genet. 1999 Jan;21:128-32). Functional studies demonstrate that the c.-34G>T mutation severely reduces the reporter activity in every cell type tested (Bisio A et al. Hum. Mol. Genet. 2010 Apr;19:1479-91). This alteration was identified in an individual with at least 3 primary melanoma diagnoses (Li C et al. Melanoma Res. 2020 06;30:247-251). In addition, this alteration has been reported in numerous families with melanoma, pancreatic cancer, and/or atypical nevi, and has been shown to segregate with disease (Liu L et al. Nat. Genet. 1999 Jan;21:128-32; Berwick M et al. Cancer Epidemiol. Biomarkers Prev. 2006 Aug;15:1520-5; Florell SR et al. J. Invest. Dermatol. 2008 Aug;128:2122-5; Larre Borges A et al. Br. J. Dermatol. 2009 Sep;161:536-41; Harland M et al. Hered. Cancer Clin. Pract. 2014 Nov;12:20; Bruno W et al. J. Am. Acad. Dermatol. 2016 Feb;74:325-32; Puig S et al. Genet. Med. 2016 Jul;18:727-36; Taylor NJ et al. J. Invest. Dermatol. 2017 12;137(12):2606-2612; Brand R et al. Cancer. 2018 Sep;124(17):3520-3527). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 21, 2023 | The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant is located in the 5' untranslated region of the CDKN2A gene (P16INK4A). A functional study has shown that this variant creates a new translation initiation AUG codon, and translation initiation from this novel site results in a truncated protein, while blocking wild-type protein expression (PMID: 9916806). This variant has been reported in over thirty individuals affected with melanoma (PMID: 9916806, 16397522, 17713569, 18025365, 19523171, 25023876, 25780468, 26581427, 26681309, 26775776, 29263814, 31567591) and has been shown to segregate with melanoma and pancreatic cancer in four different families (PMID: 9916806). This variant has been identified in 6/146754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
Melanoma and neural system tumor syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 31, 2024 | - - |
Melanoma;C0919267:Ovarian neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 14, 2021 | ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PP1 strong - |
Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Familial melanoma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This variant occurs in a non-coding region of the CDKN2A (p16INK4a) gene. It does not change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with familial melanoma (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). It is commonly reported in individuals of British ancestry (PMID: 9916806, 10738302, 16397522, 17713569, 18025365, 18337833, 19523171). ClinVar contains an entry for this variant (Variation ID: 182414). Studies have shown that this variant alters CDKN2A (p16INK4a) gene expression (PMID: 9916806, 20093296). For these reasons, this variant has been classified as Pathogenic. - |
Melanoma, cutaneous malignant, susceptibility to, 2 Other:1
risk factor, no assertion criteria provided | literature only | OMIM | Jan 01, 1999 | - - |
Computational scores
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BayesDel_noAF
Benign
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Benign
DANN
Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at