9-21971200-C-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Very_StrongPM1PM5PP5_Very_Strong

The NM_000077.5(CDKN2A):c.159G>C(p.Met53Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,597,670 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M53T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6O:1

Conservation

PhyloP100: 5.60

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_000077.5 (CDKN2A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 532294

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000077.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-21971202-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1467708.Status of the report is criteria_provided_single_submitter, 1 stars.

PP5

Variant 9-21971200-C-G is Pathogenic according to our data. Variant chr9-21971200-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21971200-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.159G>C	p.Met53Ile	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4 linkuse as main transcript	c.202G>C	p.Asp68His	missense_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.159G>C	p.Met53Ile	missense_variant	2/3	1	NM_000077.5	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.202G>C	p.Asp68His	missense_variant	2/3	1	NM_058195.4		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

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:

0.00000905

AC:

AN:

221078

Hom.:

AF XY:

0.00

AC XY:

AN XY:

123014

show subpopulations

Gnomad AFR exome

AF:

0.0000749

Gnomad AMR exome

AF:

0.00

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:

0.0000101

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000187

AC:

AN:

1445440

Hom.:

Cov.:

AF XY:

0.0000222

AC XY:

AN XY:

719514

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74368

show subpopulations

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:

0.0000113

ExAC

AF:

0.0000167

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2022	Observed in numerous individuals of various ethnicities with a personal and/or family history of melanoma and identified as a founder variant in the Scottish population (Walker 1995, MacKie 1998, Tsao 2000, Box 2001, Goldstein 2004, Lang 2005, Kannengiesser 2007, Lang 2007, Helsing 2008, Harland 2014, Sinnya 2015); Published functional studies demonstrate a damaging effect: significantly reduced binding to CDK4 compared to wild-type (Sun 1997, Monzon 1998, Becker 2001, McKenzie 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17171691, 10987867, 10861313, 16905682, 27804060, 27568332, 31653154, 17713569, 29922827, 20340136, 17492760, 11595726, 9516223, 15146471, 21507037, 18023021, 25780468, 9603434, 9416844, 15173226, 22841127, 12459645, 9389568, 8710906, 1531137, 7083179, 8595405, 26681309, 9699728, 11500805, 16307646, 26103950, 25370744, 16354195, 31567591, 32427313) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2021	The p.M53I pathogenic mutation (also known as c.159G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 159. The methionine at codon 53 is replaced by isoleucine, an amino acid with highly similar properties. This mutation has been identified in many familial melanoma kindreds and has also been shown to segregate with disease multiple large families (FitzGerald MG et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Aug;93:8541-5; Goldstein AM et al. J. Med. Genet., 2007 Feb;44:99-106; MacKie RM et al. J. Invest. Dermatol., 1998 Aug;111:269-72; Monzon et al. N Eng J Med 1998; 338(13): 879-87; Soufir N et al. Hum. Mol. Genet. 1998 Feb;7(2):209-16; Walker GJ Hum. Mol. Genet. 1995 Oct; 4(10):1845-52; Flores JF et al. Oncogene 1997 Dec;15(24):2999-3005). In a Norwegian study, it was identified in multiple probands with melanoma and pancreatic cancer (Levin T and Maehle L Fam. Cancer. 2017 04;16(2):257-265). Functional analyses of proteins harboring the p.M53I substitution have consistently demonstrated impaired binding to CDK4. In some cases, the variant protein was also shown to have reduced association with CDK6 and/or impaired growth and colony formation (Becker TM et al. Clin. Cancer Res. 2001 Oct;7(10):3282-8; Harland M et al. Hum. Mol. Genet., 1997 Nov;6:2061-7; McKenzie et al. Hum Mutat 2010; 31(6): 692-701; Sun et al. Int J Cancer 1997; 73(4): 531-6; Walker et al. Int J Cancer 1999; 82(2): 305-12). Of note, this alteration is also designated as p.M45I in published literature. Haplotype analysis strongly suggests that the p.M53I mutation is likely a founder mutation, originating in Scotland (Lang J et al. Br. J. Dermatol., 2005 Dec;153:1121-5; Lang J et al. Genes Chromosomes Cancer, 2007 Mar;46:277-87). 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	Nov 21, 2022	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces methionine with isoleucine at codon 53 of the CDKN2A (p16INK4A) protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies reported defects in CDK binding, loss of cell cycle control and inhibition of cellular growth (PMID: 9328469, 9389568, 11595726, 20340136). This variant has been reported as a Scottish melanoma founder mutation (PMID 17171691) and observed in melanoma affected families in Europe, North America, and Australia (PMID 8595405, 9328469, 9389568, 9699728, 16234564, 16307646, 16896043, 16905682) and in individual(s) with pancreatic cancer with positive family history (PMID 25356972, 32482799). This variant has been identified in 2/221078 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of CDKN2A (p16INK4A) function is a known mechanism of disease. 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

Sep 05, 2023

- -

Familial melanoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

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 replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 53 of the CDKN2A (p16INK4a) protein (p.Met53Ile). This variant is present in population databases (rs104894095, gnomAD 0.008%). This missense change has been observed in individual(s) with melanoma (PMID: 8595405, 9328469, 9699728, 16307646, 16905682, 17171691). It is commonly reported in individuals of Scottish ancestry (PMID: 8595405, 9328469, 9699728, 16307646, 16905682, 17171691). This variant is also known as c.202G>C (p.Asp68His) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 9414). 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 disruptive. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 9328469, 9389568, 11595726). 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. -

Melanoma, cutaneous malignant, susceptibility to, 2

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Uncertain

0.060

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.13

T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.43

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.013

D;D

Vest4

0.47

MVP

0.97

ClinPred

0.94

GERP RS

5.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over