rs1800586

chr9-21974861-C-Achr9-21974861-C-Gchr9-21974861-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PP5_Very_Strong BP4 BS2

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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12 O:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.
• BS2: High AC in GnomAdExome at 5 AD gene.

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: 2 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000433 AC: 5 AN: 115386 Hom.: 0 AF XY: 0.0000474 AC XY: 3 AN XY: 63326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000778

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000656 AC: 89 AN: 1357220 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 35 AN XY: 668658

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000175

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: 0.0000748

Gnomad4 OTH exome AF: 0.0000711

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

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	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. -
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. -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 29, 2023

- -

Melanoma;C0919267:Neoplasm of ovary 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

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	2.5
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800586; hg19: chr9-21974860; COSMIC: COSV58702359; COSMIC: COSV58702359;