rs45476696

chr9-21970902-C-Achr9-21970902-C-Gchr9-21970902-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The ENST00000498124.1(CDKN2A):c.457G>T(p.Glu153Ter) variant causes a stop gained, 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. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A ENST00000498124.1 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.07

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 19 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. 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 [Likely_pathogenic]. Clinvar id is 216035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21970902-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.457G>T	p.Asp153Tyr	missense_variant, splice_region_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.*101G>T		splice_region_variant, 3_prime_UTR_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.457G>T	p.Asp153Tyr	missense_variant, splice_region_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*101G>T		splice_region_variant, 3_prime_UTR_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459336 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726054

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2022	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. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 12, 2022	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. -

Melanoma-pancreatic cancer syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 08, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 20, 2023	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]. -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 11, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jan 19, 2023

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. -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

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; Invitae). 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	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.42	T;.;.;T
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	A;D;D;D;D;D;N;N;N;N;N;N
PrimateAI	Uncertain	0.52	T
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	D
GERP RS		3.3
Varity_R		0.13

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

LitVar

Other links and lift over

dbSNP: rs45476696; hg19: chr9-21970901; COSMIC: COSV58729212; COSMIC: COSV58729212;