rs45476696

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong

The NM_000077.5(CDKN2A):c.457G>T(p.Asp153Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D153N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense, splice_region

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 4.07

Publications

34 publications found

Variant links:

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]

CDKN2A Gene-Disease associations (from GenCC):

melanoma, cutaneous malignant, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
melanoma-pancreatic cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atypical multiple mole melanoma syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma and neural system tumor syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CDKN2A links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-21970902-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532292.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 9-21970902-C-A is Pathogenic according to our data. Variant chr9-21970902-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 216035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.457G>T	p.Asp153Tyr	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.*101G>T		splice_region_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2	Q8N726-1
CDKN2A	NM_058195.4 link	c.*101G>T		3_prime_UTR_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CDKN2A	ENST00000304494.10 link	c.457G>T	p.Asp153Tyr	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5	P42771-1
CDKN2A	ENST00000579755.2 link	c.*101G>T		splice_region_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1	Q8N726-1
CDKN2A	ENST00000579755.2 link	c.*101G>T		3_prime_UTR_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1	Q8N726-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

246432

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459336

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5364

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111998

Other (OTH)

AF:

0.00

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Melanoma-pancreatic cancer syndrome

Pathogenic:3

Apr 20, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12853981]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 12853981]. -

Feb 08, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 29, 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:3

Mar 04, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.457G>T pathogenic mutation (also known as p.D153Y), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 457. The amino acid change results in aspartic acid to tyrosine at codon 153, an amino acid with highly dissimilar properties. This change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. Of note, this variant is also known as c.500G>T the p14(ARF) isoform. This alteration has been identified in several kindreds with familial melanoma and/or pancreatic cancer (Ambry internal data; Moskaluk CA et al. Hum. Mutat. 1998;12(1):70; Lynch HT et al. Cancer. 2002 Jan;94(1):84-96; Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Demenais F et al. J. Natl. Cancer Inst. 2010 Oct 20;102(20):1568-83; Lucas AL et al. Cancer. 2014 Jul;120(13):1960-7; Zhen DB et al. Genet. Med. 2015 Jul;17(7):569-77). RT-PCR splicing assays of mRNA from lymphocytes indicate that this alteration results in a transcript product from the splicing of a cryptic donor site located within exon 2, splicing out 74 base pairs encoded by exon 2, as well as a transcript with complete exon 2 skipping (Ambry internal data; Rutter JL et al. Oncogene. 2003 Jul; 22(28):4444-8; Loo JC et al. Oncogene. 2003 Sep;22(41):6387-94). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Sep 12, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces aspartic acid with tyrosine at codon 153 of the CDKN2A (p16INK4A) protein. RNA studies have shown that this variant causes the both the activation of a cryptic splice donor site within exon 2 resulting in the splicing out 74 bp, and the skipping of exon 2 (PMID: 12853981, 14508519). The predicted protein products lack either 24 amino acids encoded by exon 2 or all of exon 2, both causing a frameshift in exon 3. This variant also impacts the p14ARF transcript and protein, deleting 74 bp from the 3'UTR and skipping the entire exon 2. The consequences of the p14ARF deletions are not clear but may contribute to disease in carriers. This variant has been reported in numerous individuals affected with melanoma and pancreatic adenocarcinoma (PMID: 10627132, 11815963, 11815963, 12853981, 21150883, 24737347, 25356972, 28726808, 29922827). It has been shown that this variant segregates with disease in family studies (PMID: 11815963). 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. -

Aug 15, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The CDKN2A c.457G>T (p.Asp153Tyr) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict damaging outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively). This variant leads to substitution of the last nucleotide in exon 2 and 5/5 splice prediction tools predict a significant impact on normal splicing. This variant is absent in 118670 control chromosomes from ExAC. This germline variant has been found in familial cases with cutaneous malignant melanoma and pancreatic cancer, including evidence of cosegregation with disease ((Lynch_2002, Loo_2003, Rutter_2003, McWilliams_2011, Lucas_2014). Functional studies have shown that this variant causes aberrant splicing in a similar manner with another splice-site variant c.457+1G>T. This variant leads to activation of a cryptic donor site located within exon 2, thus splicing out 74 bp encoded by exon 2. The predicted protein product of the mutant lacks 24 amino acids encoded by exon 2 and possesses a frameshift in exon 3 that yields six amino acids followed by a termination codon (Loo_2003, Rutter_2003). Multiple clinical diagnostic laboratories in ClinVar have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided

Pathogenic:2

Jan 19, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with melanoma (PMID: 12853981 (2003), 14508519 (2003), 16905682 (2007), 20539244 (2010), 20876876 (2010), 21150883 (2011), 29263814 (2016), 34028844 (2021)), and individuals with pancreatic cancer (PMID: 21150883 (2011), 25356972 (2015), 28726808 (2018), 29263814 (2016), 29922827 (2018)). Functional splicing assays demonstrate this variant causes aberrant splicing and skipping of exon 2 which creates a premature stop codon in exon 3 (PMID: 12853981 (2003), 14508519 (2003)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CDKN2A: PP1:Strong, PVS1:Strong, PM2, PS4:Moderate -

Melanoma and neural system tumor syndrome

Pathogenic:1

Sep 11, 2022

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial melanoma

Pathogenic:1

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 153 of the CDKN2A (p16INK4a) protein (p.Asp153Tyr). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 10627132, 12853981, 14508519, 16905682, 20539244, 20876876, 21150883, 25356972; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 216035). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change results in partial exon exclusion and introduces a new termination codon (PMID: 12853981, 14508519). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.066

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.42

T;.;.;T

MetaRNN

Benign

0.35

T;T;T;T

MetaSVM

Benign

-0.81

PhyloP100

4.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.1

N;.;.;.

REVEL

Uncertain

0.44

Sift

Benign

0.045

D;.;.;.

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.58

P;.;.;.

Vest4

0.30

MutPred

0.39

Gain of phosphorylation at D153 (P = 0.0177);.;.;.;

MVP

0.96

ClinPred

0.78

GERP RS

3.3

PromoterAI

-0.052

Neutral

(source)

Varity_R

0.13

Mutation Taster

=15/185

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.76

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over